Nasal stimulation for rhinitis, nasal congestion, and ocular allergies

ABSTRACT

Described here are devices, systems, and methods for treating one or more conditions, such as allergic rhinitis, non-allergic rhinitis, nasal congestion, ocular allergy, and/or symptoms associated with these conditions, by providing stimulation to nasal or sinus tissue. In some variations, the handheld devices may have a stimulator body and a stimulator probe having one or more nasal insertion prongs, and the nasal insertion prongs may be configured to deliver an electrical stimulus to the tissue.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation Application of U.S. patentapplication Ser. No. 15/438,577, filed on Feb. 21, 2017 which claimspriority to U.S. Provisional Application No. 62/297,734, filed Feb. 19,2016, and titled “NASAL STIMULATION FOR RHINITIS, NASAL CONGESTION, ANDOCULAR ALLERGIES,” the contents of each are incorporated by referenceherewith in their entirety.

FIELD

Described herein are methods for treating allergic rhinitis,non-allergic rhinitis, nasal congestion, ocular allergy, and/or symptomsassociated with these conditions by delivering an electrical stimulus.

BACKGROUND

Patients with allergic and non-allergic rhinitis and nasal congestionoften suffer from inflammation of the nasal membranes that can causenumerous symptoms and complications. These same patients may frequentlyalso suffer from other types of allergies and immunoglobulin E(IgE)-mediated disorders, including ocular allergies. Typical treatmentsmay include pharmacologic therapy, such as intranasal steroids, oralantihistamines, and anti-IgE for allergic rhinitis. However, it would bedesirable to have a non-pharmacologic, non-invasive treatment for theseconditions for use alone or in combination with pharmacologic therapy.

Allergic rhinitis in particular is an IgE-mediated inflammatory nasaldisorder that involves hyperactive nasal mucosa, obstruction of thenasal passages, and symptoms of rhinorrhea, sneezing, nasal pruritus,and congestion. Allergic rhinitis is also commonly associated withconjunctivitis, itchy palate, and aggravation of comorbid asthma.Traditionally, allergic rhinitis has been classified as perennial, withsymptoms occurring year round, or seasonal, with symptoms occurring atparticular times of the year. Perennial symptoms are most commonlyassociated with dust mites, cockroaches, and molds, whereas seasonalsymptoms may be induced by pollens.

Allergic rhinitis currently affects 10% to 25% of the populationworldwide, and 20 to 40 million people in the United States annually,including 10% to 30% of adults and up to 40% of children. Furthermore,incidence of allergic rhinitis seems to be increasing globally. Themanagement of allergic rhinitis remains challenging because of the sideeffects of existing medication classes and because of their variableeffectiveness. The latter reflects the variable nature of allergicrhinitis in the general population. There is therefore an unmet need fora safe and effective non-pharmacological method for treating allergicrhinitis.

BRIEF SUMMARY

Described herein are methods for treating rhinitis (allergic rhinitis,non-allergic rhinitis), nasal congestion, runny nose, ocular allergy,and/or symptoms associated with these conditions. Some methods fortreating rhinitis described herein may comprise delivering an electricalstimulus via an electrode to treat rhinitis in a patient in needthereof. The rhinitis may be allergic rhinitis or non-allergic rhinitis.The electrode may be in contact with nasal tissue of the patient duringdelivery of the electrical stimulus. In some variations, the electricalstimulus is delivered in response to one or more symptoms of rhinitis.The one or more symptoms of rhinitis may comprise one or more ofitching, sneezing, congestion, runny nose, post-nasal drip, mouthbreathing, coughing, fatigue, headache, anosmia, phlegm, throatirritation, periorbital puffiness, watery eyes, ear pain, and fullnesssensation. In other variations of the method, the electrical stimulus isdelivered more than once per day on a scheduled basis. In somevariations of a method for treating rhinitis, the nasal tissue to whichthe electrical stimulus is delivered is nasal mucosa. The nasal mucosamay be adjacent to the nasal septum. In some variations of the method,the electrode may be a hydrogel electrode. The electrode may beelectrically connected to a control subsystem configured to control theelectrical stimulus delivered via the electrode. The electrode may bepositioned on a stimulator probe and the control subsystem is positionedin a stimulator body, and the stimulator probe may be releasablyconnected to the stimulator body. The electrical stimulus may be abiphasic pulse waveform.

Also described here are methods for treating rhinitis, comprisingdelivering an electrical stimulus to nasal tissue of a subject toimprove rhinitis of the subject, where the electrical stimulus isdelivered by an electrode of a stimulator comprising a control subsystemto control the electrical stimulus. The rhinitis may be allergicrhinitis or non-allergic rhinitis. In some variations, the electricalstimulus may be delivered in response to one or more symptoms ofrhinitis. The one or more symptoms of rhinitis may comprise one or moreof itching, sneezing, congestion, runny nose, post-nasal drip, mouthbreathing, coughing, fatigue, headache, anosmia, phlegm, throatirritation, periorbital puffiness, watery eyes, ear pain, and fullnesssensation. In some variations, the electrical stimulus is pulsed. Insome variations of the method, the electrical stimulus may be deliveredat least once daily during a treatment period. The electrical stimulusmay be delivered on a scheduled basis during the treatment period. Insome variations, the electrical stimulus may be a biphasic pulsewaveform. The biphasic pulse waveform may be symmetrical, may havevarying peak to peak amplitude, and/or may have a varying frequency. Insome variations of the method, the stimulator may be configured to behand held. In some variations, delivering the electrical stimulus tonasal tissue may activate the ophthalmic branch of the trigeminal nerve.In some variations, delivering the electrical stimulus may activate theanterior ethmoidal nerve. In some variations, delivering the electricalstimulus may activate the internal branches of the infraorbital nerve.In some variations, delivering the electrical stimulus may activate thesuperior branches of the greater palatine nerve. In some variations,delivering the electrical stimulus may activate the septal nerve. Insome variations, delivering the electrical stimulus may activate theposterior superior lateral nasal branch of the maxillary nerve.

Also described here are methods for treating nasal congestion,comprising delivering an electrical stimulus via an electrode to treatnasal congestion in a patient in need thereof. The electrode may be incontact with nasal tissue of the patient during delivery of theelectrical stimulus. In some variations, the electrical stimulus may bedelivered in response to one or more symptoms of nasal congestion. Theone or more symptoms of nasal congestion may comprise difficulty withnasal breathing, ear fullness, facial pain, and/or facial andintracranial pressure. In other variations, the electrical stimulus isdelivered more than once per day on a scheduled basis. The nasal tissuemay be nasal mucosa, which in some instances may be adjacent to thenasal septum. The electrode in contact with the tissue may be a hydrogelelectrode. The electrode may be electrically connected to a controlsubsystem configured to control the electrical stimulus delivered viathe electrode. The electrode may be positioned on a stimulator probe andthe control subsystem is positioned in a stimulator body, and thestimulator probe may be releasably connected to the stimulator body. Insome variations, the electrical stimulus may be a biphasic pulsewaveform.

Also described here are methods for treating nasal congestion comprisingdelivering an electrical stimulus to nasal tissue of a subject toimprove nasal congestion of the subject, wherein the electrical stimulusis delivered by an electrode of a stimulator comprising a controlsubsystem to control the electrical stimulus. The electrical stimulusmay be delivered in response to one or more symptoms of nasalcongestion. The one or more symptoms of nasal congestion may comprisedifficulty with nasal breathing, ear fullness, facial pain, and/orfacial and intracranial pressure. In other variations, the electricalstimulus may be delivered at least once daily during a treatment period.In some of these variations, the electrical stimulus may be delivered ona scheduled basis during the treatment period. In some variations of themethod, the electrical stimulus is pulsed. The electrical stimulus maybe a biphasic pulse waveform. The biphasic pulse waveform may besymmetrical, may have varying peak to peak amplitude, and/or may have avarying frequency. In some variations of the method, the stimulator maybe configured to be hand held. In some variations, delivering theelectrical stimulus to nasal tissue may activate the ophthalmic branchof the trigeminal nerve. In some variations, delivering the electricalstimulus may activate the anterior ethmoidal nerve. In some variations,delivering the electrical stimulus may activate the internal branches ofthe infraorbital nerve. In some variations, delivering the electricalstimulus may activate the superior branches of the greater palatinenerve. In some variations, delivering the electrical stimulus mayactivate the septal nerve. In some variations, delivering the electricalstimulus may activate the posterior superior lateral nasal branch of themaxillary nerve.

Also described here are methods for treating ocular allergy comprisingdelivering an electrical stimulus via an electrode to treat ocularallergy in a patient in need thereof. The electrode may be in contactwith nasal tissue of the patient during delivery of the electricalstimulus. In some variations of the method, the electrical stimulus isdelivered in response to one or more symptoms of ocular allergy. The oneor more symptoms of ocular allergy may comprise one or more of swelling,puffiness, itching, tearing, and discharge. In other variations, theelectrical stimulus is delivered more than once per day on a scheduledbasis. The nasal tissue may be nasal mucosa, which in some instances maybe adjacent to the nasal septum. The electrode in contact with thetissue may be a hydrogel electrode. The electrode may be electricallyconnected to a control subsystem configured to control the electricalstimulus delivered via the electrode. The electrode may be positioned ona stimulator probe and the control subsystem is positioned in astimulator body, and the stimulator probe may be releasably connected tothe stimulator body. In some variations, the electrical stimulus may bea biphasic pulse waveform.

Also described here are methods for treating ocular allergy comprisingdelivering an electrical stimulus to nasal tissue of a subject toimprove ocular allergy of the subject, where the electrical stimulus isdelivered by an electrode of a stimulator comprising a control subsystemto control the electrical stimulus. The electrical stimulus may bedelivered in response to one or more symptoms of ocular allergy. The oneor more symptoms of ocular allergy may comprise one or more of swelling,puffiness, itching, tearing, and discharge. In other variations, theelectrical stimulus may be delivered at least once daily during atreatment period. In some of these variations, the electrical stimulusmay be delivered on a scheduled basis during the treatment period. Insome variations of the method, the electrical stimulus is pulsed. Theelectrical stimulus may be a biphasic pulse waveform. The biphasic pulsewaveform may be symmetrical, may have varying peak to peak amplitude,and/or may have a varying frequency. In some variations of the method,the stimulator may be configured to be hand held. In some variations,delivering the electrical stimulus to nasal tissue may activate theophthalmic branch of the trigeminal nerve. In some variations,delivering the electrical stimulus may activate the anterior ethmoidalnerve. In some variations, delivering the electrical stimulus mayactivate the internal branches of the infraorbital nerve. In somevariations, delivering the electrical stimulus may activate the superiorbranches of the greater palatine nerve. In some variations, deliveringthe electrical stimulus may activate the septal nerve. In somevariations, delivering the electrical stimulus may activate theposterior superior lateral nasal branch of the maxillary nerve.

Also described here are methods of treatment comprising delivering anelectrical stimulus via an electrode to treat allergic rhinitis in apatient in need thereof. The electrode may be in contact with nasaltissue of the patient during delivery of the electrical stimulus. Insome variations, the electrical stimulus delivery may treat allergicrhinitis as determined by a reduction in a symptom of allergic rhinitis.Such symptoms may include nasal itching, nasal congestion, rhinorrhea,or sneezing. In other variations, the electrical stimulus may treatallergic rhinitis as determined by a reduction in nasal inflammation; asdetermined by an increase in peak nasal inspiratory flow; as determinedby an initial transient increase in nasal secretions, followed by areduction in nasal secretions; as determined by normalization intemperature of a nasal area; or as determined by a decrease infractional exhaled nitric oxide. In some variations, the method mayfurther comprise expelling accumulated material in the nasalpassageways.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A, 1B, 1C, 1D, 1E show perspective, front, back, cut-away back,and cut-away side views, respectively, of an illustrative variation of ahandheld stimulator.

FIG. 2 shows a block diagram schematically representing a variation of astimulator.

FIG. 3A and FIGS. 3B-3C show perspective and exploded views,respectively, of a stimulator body suitable for the handheld stimulatorsdescribed here. FIG. 3D shows a perspective view of a portion of thestimulator body of FIGS. 3A-3C.

FIGS. 4A-4C illustrate relevant anatomical locations.

FIGS. 5A, 5B, 5C, 5D, and FIGS. 5E-5F depict back, side, cut-away back,cut-away top, and perspective views, respectively, of a stimulator probesuitable for the handheld stimulators described here. FIG. 5G depicts aperspective view of a rigid support of the stimulator probe of FIGS.5A-5F.

FIG. 6 shows a cross-sectional view of a stimulator probe positioned inthe nose of a user.

FIG. 7 depicts a perspective view of the stimulator of FIGS. 1A-1E withthe stimulator probe disconnected from the stimulator body.

FIG. 8 illustrates a schematic diagram of stimulator circuitry.

FIGS. 9A and 9B show perspective and front views, respectively, of thehandheld stimulator of FIGS. 1A-1E with an attached cap. FIG. 9C shows aperspective view of a cap.

FIGS. 10A-10D depict portions of a stimulator system comprising astimulator and a base station. FIG. 10A shows a front view of thestimulator body docked in the base station, while FIGS. 10B, 10C, and10D depict side, back, and top views, respectively, of the base station.

FIGS. 11A-11B illustrate placement of an interventional stimulator and acontrol stimulator.

DETAILED DESCRIPTION OF THE INVENTION

Described here are devices, systems, and methods for treating one ormore conditions, including rhinitis, nasal congestion, ocular allergy,and/or symptoms associated with these conditions. Generally, the devicesand systems may be configured to stimulate nasal or sinus tissue.

Devices

The stimulation described herein may in some variations be delivered bya handheld stimulator configured to deliver an electrical stimulus tonasal tissue. In some variations, the devices may comprise a stimulatorbody and a stimulator probe, where the stimulator probe comprises one ormore nasal insertion prongs. FIGS. 1A, 1B, 1C, 1D, 1E show perspective,front, back, cut-away back, and cut-away side views, respectively, of anillustrative variation of a handheld stimulator 100, respectively. FIG.2 shows a block diagram schematically representing the stimulator 100.As shown in FIGS. 1A-1E, the stimulator 100 may comprise a stimulatorbody 102 and a stimulator probe 104. Generally, the stimulator body 102may be configured to generate a stimulus that may be delivered to thesubject. The stimulator body 102 may comprise a front housing 138, backhousing 140, and proximal housing 142, which may fit together to definea body cavity 154. The body cavity 154 may contain a control subsystem136 and a power source 152, which together may generate and control thestimulus.

The stimulus may be delivered to a subject via the stimulator probe 104.In some variations the stimulator body 102 and stimulator probe 104 maybe reversibly attachable, as described in more detail herein. In othervariations, the stimulator probe may be permanently connected to thestimulator body. Some or all of the stimulator 100 may be disposable. Invariations where the stimulator body is permanently attached to thestimulator probe, the entire stimulator may be disposable. In othervariations, one or more portions of the stimulator 100 may be reusable.For example, in variations where the stimulator probe 104 is releasablyconnected to the stimulator body 102, the stimulator body 102 may bereusable, and the stimulator probe 104 may be disposable andperiodically replaced, as described in more detail herein.

The stimulator probe 104 may comprise at least one nasal insertionprong, which may be configured to be at least partially inserted intothe nasal cavity of a subject or patient. In the handheld stimulatorvariation shown in FIGS. 1A-1E, the stimulator probe 104 may comprisetwo nasal insertion prongs 106 and 108. The stimulator probe 104 mayfurther comprise ridges 120, which may allow the patient to more easilygrip the probe 104.

In some variations, the stimulus may be electrical. In these instances,each nasal insertion prong may comprise at least one electrode. Asshown, the probe 104 may comprise a first electrode 110 on nasalinsertion prong 106 and a second electrode 112 on nasal insertion prong108. As shown in the cut-away view of the stimulator 100 in FIG. 1D, theelectrodes 110 and 112 may be connected to leads 130 and 132 locatedwithin prongs 106 and 108, respectively. The leads 130 and 132 may inturn be connected to connectors 122 and 124, respectively. Connectors122 and 124 may extend through lumens 208 and 210 in the proximalhousing 142, and may connect directly or indirectly to the controlsubsystem 136 and power source 152. As such, the electrical stimulus maytravel from the control subsystem 136 through the connectors 122 and124, through the leads 130 and 132, and through the electrodes 110 and112.

The stimulator body 102 may comprise a user interface 230 comprising oneor more operating mechanisms to adjust one or more parameters of thestimulus, as described in more detail herein. The operating mechanismsmay provide information to the control subsystem 136, which may comprisea processor 232, memory 234, and/or stimulation subsystem 236. In somevariations, the operating mechanisms may comprise first and secondbuttons 114 and 116. In some variations, pressing the first button 114may turn on the stimulator and/or change one or more parameters of thestimulus (e.g., increase the intensity of the stimulus, change thestimulation pattern, or the like), while pressing the second button 116may turn off the stimulator and/or change one or more parameters of thestimulus (e.g., decrease the intensity of the stimulus, change thestimulation pattern, or the like). Additionally or alternatively, theuser interface may comprise one or more feedback elements (e.g., basedon light, sound, vibration, or the like). As shown, the user feedbackelements may comprise light-based indicators 118, which may provideinformation to the user, as described in more detail herein.

Stimulator Body

Turning to the stimulator body, FIG. 3A and FIGS. 3B-3C show aperspective view and exploded views, respectively, of the stimulatorbody 102. The stimulator body 102 may have any suitable shape. In somevariations, it may be desirable for the stimulator body 102 to be shapedsuch that it can be easily gripped by a user, such that it can be heldwith one hand, such that it can be placed upright on a surface, and/orsuch that it can be easily and/or discretely carried in a pocket orpurse. As shown in FIG. 3A, the stimulator body 102 may have a truncatedovoid shape. However, it should be appreciated that the stimulator bodymay have other shapes. The proximal end of the stimulator body 102(formed by proximal housing 142) may have a shape that is complementaryto the bottom of the stimulator probe 104, as described in more detailherein.

As mentioned above, the stimulator body may comprise a housing formed bya front housing 138, a back housing 140, and a proximal housing 142.These may fit together to form the exterior of the stimulator body. Thefront housing 138 and back housing 140 may fit together with anysuitable attachment mechanism. For example, the front 138 and back 140housings may fit together with a tongue-and-groove joint. The proximalhousing 142 may comprise a proximal portion 204, which may fit over theproximal ends of the front and back housings 138 and 140, and a distalportion 206, which may fit within a portion of the stimulator probe 104,as described in more detail herein. The housing formed by the front 138,back 140, and proximal 142 housings may comprise any number of suitableopenings for elements of the stimulator body. For example, the proximalhousing 142 may comprise two lumens 208 and 210 that may be configuredto receive connectors 122 and 124, as described in more detail herein.The front housing 138 may comprise an opening configured to receive aportion of the user interface 230, as described in more detail herein.It should be appreciated that while the housing is described here ascomprising front, back, and proximal housings, the housing may beconstructed from any number of separate housing components (e.g., two,three, four, five, or more).

In some instances, it may be desirable for the stimulator body to besealed, such that it may be waterproof or the like. In some of theseinstances, when the housing comprises a front housing 138, back housing140, and proximal housing 142, the three housing portions may attach soas to be watertight. For example, the tongue-and-groove joint describedabove may be watertight. In some variations, the stimulator body 102 mayfurther comprise one or more seals located at the interface between thefront housing 138 and the back housing 140, and/or between the front 138and back 140 housings and the proximal housing 142. In variations inwhich the housing comprises openings for other elements of thestimulator body (e.g., connectors 122 and 124, a release mechanism, orthe like), the interface between those elements and the stimulatorhousing may be watertight, and/or may comprise seals.

In some variations, it may be desirable for each of the front housing138, back housing 140, and proximal housing 142 to be formed from thesame material in order to improve the ability of the front housing 138,back housing 140, and proximal housing 142 to maintain a tight seal andto exhibit similar expansion/contraction properties with changes intemperature. In some variations, the front housing 138, back housing140, and top housing 142 may each comprise a rigid material, such as arigid plastic. For example, the front 138, back 140, and top 142housings may comprise a thermoplastic such as acrylonitrile butadienestyrene (ABS), polycarbonate, polyetherimide (e.g., ULTEM™polyetherimide). However, the housing may comprise any suitable materialor materials. Furthermore, it should be appreciated that in somevariations the front housing 138, back housing 140, and/or proximalhousing 142 may comprise different materials.

In some variations the housing may comprise an alignment mechanism. Thealignment mechanism may assist in aligning the stimulator body with thestimulator probe in variations in which the stimulator body andstimulator probe are detachable, and/or it may assist in keeping thestimulator body and stimulator probe connected. Additionally oralternatively, in which the stimulator system comprises a base station(as described in more detail herein), it may assist in aligning thestimulator body with the base station in variations and/or it may assistin keeping the stimulator body and the base station connected. Invariations in which the stimulator is configured to be attached to acharging cable, the alignment mechanism may assist in aligning thestimulator or a portion of the stimulator with a charging cable and/orkeeping the stimulator and charging cable attached. In some variations,the alignment mechanism may comprise a magnet. FIG. 3D shows aperspective view of a portion of the stimulator body 102. A magnet 134may be connected to the interior surface of the proximal housing 142 asshown. In other variations, a magnet may be connected to the interior ofanother portion of the housing, or to the exterior of any portion of thehousing. In variations in which the magnet 134 may assist in aligningthe stimulator body 102 with the stimulator probe 104, the stimulatorprobe 104 may comprise a magnet or ferromagnetic material in acorresponding location. In variations in which the magnet 134 may assistin aligning the stimulator body 102 to a base station, the base stationmay comprise a magnet or ferromagnetic material in a correspondinglocation.

In some variations the housing may comprise a weight. It may in someinstances be desirable for the stimulator to have a sufficient weightsuch that it has a substantial feel when held by a user. In somevariations, the alignment mechanism (e.g., a magnet) may further serveas a weight. Additionally or alternatively, the weight may comprise adense material or materials (e.g., iron or steel). The weight may belocated in any suitable location within the housing. In some instances,the weight may be attached to the interior of the housing, to a printedcircuit board comprising the control subsystem (described in more detailbelow), or threaded within pins holding a printed circuit board in place(e.g., pins 144 in stimulator body 102).

In some variations, the stimulator bodies described here may comprisefeatures to assist the user in holding the device. For example, one ormore portions of the stimulator may comprise ridges on both sides of thestimulator body. These ridges may act as grips for the user to holdonto. It should be appreciated that any of the stimulator bodiesdescribed here may comprise any suitable features to assist the user inholding the device, such as any texturized surface, a high-frictionmaterial (e.g., rubber), indentations, or the like.

In instances where the stimulators described here comprise a userinterface, the user interface may comprise one or more operatingmechanisms, which may allow the user to control one or more functions ofthe stimulator. For example, the operating mechanisms may allow the userto power the device on or off, start or stop the stimulus, change theintensity of the stimulus, change the duration of the stimulus, changethe stimulus pattern, or the like. In some variations, the operatingmechanisms may be able to activate or deactivate different functions,and/or may be able to change different parameters, based on their mannerof operation (e.g., pressing a button briefly, pressing a button for aprolonged period, pressing a button with a particular pattern ofpressing actions, rotating a dial by different angles or differentspeeds). Each of the one or more operating mechanisms may be anysuitable structure, such as but not limited to a button, slider, lever,touch pad, knob, or deformable/squeezable portion of the housing, and astimulator may comprise any combination of different operatingmechanisms.

In one variation, the one or more operating mechanisms may comprise oneor more buttons. The stimulator body 102, for example, may comprise twobuttons 114 and 116. In the variation shown, the two buttons 114 and 116may be located on a single a flexible membrane 212. The flexiblemembrane 212 may comprise any suitable material or materials, such asbut not limited to a flexible polymer, such as a thermoplastic elastomer(e.g., a thermoplastic elastomer alloy (e.g., VERSAFLEX™ thermoplasticelastomer), thermoplastic polyurethane, or the like), silicone, or thelike. In some variations in which the flexible membrane is locatedwithin the front housing 138, the flexible membrane 212 may be attachedto the front housing 138 such that they are chemically bound. In somevariations, they may be connected via overmolding, transfer molding, ortwo-shot molding. However, it should be appreciated that the flexiblemembrane 212 may be attached to the housing in any other suitablemanner, such as via bonding.

The flexible membrane 212 may be separated into two buttons 114 and 116by a divider 150. As shown in FIGS. 1E and 3C, the divider 150 mayextend interiorly into the body cavity 154 from the interior surface ofthe flexible membrane 212. The end of the divider 150 may press againsta fixed surface within the body cavity 154 of the stimulator body 154.For example, the end of the divider 150 may press against a portion ofthe printed circuit board (PCB) (128) that forms the control subsystem136. The divider 150 may thus serve as an inflection point on theflexible membrane 212, such that each of the two buttons 114 and 116 maybe pressed separately by the user. The divider 150 may also serve toresist separation between the flexible membrane 212 and the housing(e.g., by breaking the adhesion between the housing and the flexiblemembrane) by limiting the movement of the flexible membrane 212 into thebody cavity 154.

If the user presses one of buttons 114 or 116, the movement of thebutton may be transferred to the control subsystem 136. As shown in FIG.3C, the interior surface of the flexible membrane 212 may comprise tworaised surfaces 214 and 216 on the interior surface of buttons 114 and116, respectively. When button 114 or 116 is depressed, thecorresponding raised surface 214 or 216 may press against PCB button 146or 148 (shown in FIG. 3B), respectively, located in the printed circuitboard 128, in order to transmit information to the control subsystem136. While the stimulator body 102 is shown as having two buttons formedon a single flexible membrane, it should be appreciated that in othervariations, two or more buttons may be separately formed.

In stimulator body 102, pressing the top button 114 may power on thestimulator 100 when the stimulator 100 is off. In some variations inwhich the stimulator is capable of differing stimulus intensities, thestimulator may be powered on to the last stimulus intensity from beforethe stimulator was powered off. When the stimulator 100 is on, pressingthe top button 114 may increase the intensity of the stimulus (forexample, when the stimulus is electrical, pressing the top button 114may increase the amplitude of the stimulus waveform). Conversely,pressing the bottom button 116 may decrease the intensity of thestimulus (for example, when the stimulus is electrical, pressing thebottom button 116 may decrease the amplitude of the stimulus waveform).Pressing the bottom button 116 also may in some instances power off thestimulator 100. For example, pressing and holding the bottom button 116may power off the stimulator 100; or additionally or alternatively,pressing the bottom button 116 when the stimulus intensity is at itslowest level may power off the stimulator 100. However, it should beappreciated that additionally or alternatively, the stimulator 100 maypower off without user input (e.g., after a period of idle time). Insome variations, the stimulator 100 may provide feedback to the user toindicate that the buttons are being pressed (or that other operatingmechanisms are being operated). For example, pressing the buttons oroperating any of a stimulator's operating mechanisms may be accompaniedby a sound, vibration, tactile click, light, or the like, but need notbe. It should be appreciated that the operating mechanisms of thestimulators described here may have any number of other suitableconfigurations.

Furthermore, the stimulators may be configured to provide feedback orotherwise convey information to a user. For example, in stimulator 100,the user interface 230 may comprise one or more light-based statusindicators 118. The light-based status indicators 118 may comprise oneor more light sources (e.g., LEDs) located on the printed circuit board128, which may be connected to or located near light-transmittingelements 158 on the front housing 138. The light-transmitting elements158 may transmit light from a light source on the printed circuit board128 to the exterior of the housing, where it may be perceived by a user.In some variations, the light-transmitting elements 158 may comprisefiber optics (e.g., light pipes). In other variations, thelight-transmitting elements 158 may comprise translucent or transparentepoxy) in the front housing 138.

Generally, the control subsystem of the stimulators described herein maybe configured to control a stimulus to be delivered to a subject via thestimulator probe. The control subsystem may be contained within thehousing the stimulator. The control subsystem may be connected to theoperating mechanisms of the stimulator (e.g., the buttons), which mayallow the control subsystem to receive input from a user. The controlsubsystem may also be connected to mechanisms configured to providefeedback or otherwise convey information to a user. In some variations,such as stimulator 100, the control subsystem 136 may be located on aprinted circuit board 128. When the control subsystem 136 is located ona printed circuit board 128, the printed circuit board 128 may be fixedwithin the body cavity 154 of the stimulator body 102 in any suitablemanner. In some variations, the printed circuit board 128 may be held inplace relative to the housing by pins 144. As shown in FIG. 3B, theinterior surface of back housing 140 may comprise four pins 144. Thepins 144 may be configured to fit through corresponding openings 156 inthe printed circuit board 128, and may be further configured to fit intoreceiving recesses 238 in the front housing 138. It should beappreciated that in other variations in which the printed circuit boardis secured by pins, the housing may comprise any number of pins 144,which may be located on any portion of the housing.

The control subsystem 136 may include any circuitry or other componentsconfigured to operate the stimulators as described here. In somevariations the control subsystem may comprise a processor 232, memory234, and/or a stimulation subsystem 236. Generally, the processor may beconfigured to control operation of the various subsystems of the controlsubsystem. For example, the processor 232 may be configured to controlthe stimulation subsystem 236 to control parameters of the stimulationprovided by the stimulation subsystem 236. The memory 234 may beconfigured to store programming instructions for the stimulator, and theprocessor 232 may use these programming instructions in controllingoperation of the stimulator. The stimulation subsystem 236 may beconfigured to generate a stimulation signal and deliver the stimulationsignal to a patient via the stimulator probe. In other variations, thecontrol subsystem 136 may comprise a finite state machine.

In some variations, the control subsystem 136 may comprise adetection/recording subsystem. In these variations, thedetection/recording subsystem may be configured to monitor one or moreparameters of a subject (e.g., subject impedance), the stimulationdelivered to the subject (e.g., date and time of stimulation, durationof the stimulation, amplitude of the stimulation signal, pulse width,frequency), and/or the stimulator itself (e.g., diagnostic data). Thedetection/recording subsystem may record some or all of this data to thememory. Additionally or alternatively, the control subsystem 136 may beconfigured to accept and record user input regarding subjectsymptomology, subject activity, or the like. Additionally oralternatively, the control subsystem may comprise a communicationssubsystem. The communication subsystem may be configured to facilitatecommunication of data and/or energy between the stimulator and anexternal source.

The control subsystem may in some variations comprise safety mechanisms,such as limits on the voltage, current, frequency, and duration of thestimulus when the stimulus is electrical. In some variations, some ofthese safety mechanisms may be part of the stimulation subsystem. Forexample, the stimulation subsystem 236 of the control subsystem 136 ofstimulator 100 may limit the voltage and current that may be deliveredto the patient. In some variations, the voltage may be limited by avoltage regulator. In some of these variations, the voltage limit may bebetween about 1 V and about 100 V. In some of these variations, thevoltage limit may be between about 5 V and 50 V, between about 10 V and25 V, or between about 15 V and 20 V. In some variations, the voltagemay be regulated via a boost regulator connected to the power source152, but it should be appreciated that any suitable voltage regulatormay be used. In some variations, the current may be limited by aresistor in series with the load or a current-limiting transistor, orany other suitable combinations of elements. In some variations, thecurrent limit may be about between about 1 mA to about 30 mA, betweenabout 5 mA to about 20 mA, or about 10 mA. In some variations, thestimulation subsystem 236 may be capacitively coupled by one or moreseries capacitors on the output. This capacitive coupling may prevent DCcurrents from being applied to the patient, and may limit the totalcharge injection and pulse duration.

Additionally or alternatively, some or all of the safety mechanisms ofthe control subsystem 136 may be part of the processor 232. For example,the processor 232 may comprise software that limits the frequency towithin an allowed range. In some variations, the frequency may belimited to between about between about 0.1 Hz and about 200 Hz, betweenabout 10 Hz and about 60 Hz, between about 25 Hz and about 35 Hz,between about 50 Hz and about 90 Hz, between about 65 Hz and about 75Hz, between about 130 Hz and about 170 Hz, between about 145 Hz andabout 155 Hz, or between about 145 Hz and about 155 Hz. Additionally oralternatively, the processor 232 may comprise software that limits thestimulus intensity (e.g., the current or voltage). In some of thesevariations, the voltage limit may be between about 5 V and 50 V, betweenabout 10 V and 25 V, or between about 15 V and 20 V. In some variations,the current limit may be about between about 1 mA to about 30 mA,between about 5 mA to about 20 mA, or about 10 mA. The processor 232 mayadditionally or alternatively comprise software that limits the stimulusduration. In some variations, the duration may be limited to about 1minute, about 2 minutes, about 3 minutes, about 5 minutes, about 10minutes, or the like. In some variations in which the stimulator probe104 is removably connected to the stimulator body 102, the controlsubsystem 136 may prevent the delivery of current by the stimulationsubsystem 236 when the stimulator probe 104 is disconnected from thestimulator body 102. Additionally or alternatively, the controlsubsystem 136 may prevent delivery of current by the stimulationsubsystem 236 when the stimulator probe 104 is not in contact with apatient's tissue.

The stimulator may comprise a power source. The power source may be anysuitable power supply capable of powering one or more functions of thestimulator, such as one or more batteries, capacitors, or the like. Asshown in FIGS. 3C-3D, in some variations the power source may comprise alithium coin cell battery 152. The battery 152 may be secured in placevia any suitable method, such as a clip 160 attached to the printedcircuit board 128 comprising the control subsystem 136. In somevariations, the power source may be rechargeable.

While the stimulator body 102 comprises a power source, in othervariations the stimulator body need not comprise a power source. In somevariations, the stimulator body may comprise a port, cord, or othermechanism for connecting the stimulator to an external power source(such as a wall outlet or separate battery pack), which in turn may beused to power one or more portions of the stimulator. In some othervariations, such a port, cord, or other mechanism may be used torecharge a rechargeable power source. The stimulator body 102 maycomprise such a port (e.g., a USB port) at any suitable location, suchas between the connectors 122 and 124 on the proximal housing 142, onthe back housing 140, on the front housing 138, or at the proximal endof the stimulator body 102 between the front 138 and back housings 140.

Other variations and features of stimulator bodies and componentsthereof are described in U.S. application Ser. No. 14/256,915, filedApr. 18, 2014, and titled “NASAL STIMULATION DEVICES AND METHODS,” whichis hereby incorporated by reference in its entirety.

Stimulator Probe

The stimulator probe of the stimulator may comprise one or more nasalinsertion prongs, which may be configured to extend at least partiallyinto a nasal cavity of a subject. FIGS. 5A, 5B, 5C, 5D, and FIGS. 5E-5Fdepict back, side, cut-away back, cut-away top, and perspective views,respectively, of the stimulator probe 104 of stimulator 100. As shownthere, the stimulator probe 104 may comprise a first nasal insertionprong 106 and a second nasal insertion prong 108. The first and secondprongs 106 and 108 may be connected via a base member 126. The basemember 126 may be configured to hold at least a portion of the first andsecond prongs in fixed relation to each other.

The nasal insertion prongs 106 and 108 may generally be configured to beinserted a subject's nostrils. As shown in FIGS. 5A-5F, each nasalinsertion prong 106 and 108 may comprise an elongate portion 162 and164, respectively. Each elongate portion 162 and 164 may have at itsdistal end a distal portion 176 and 178. In some variations, the distalportions 176 and 178 may have a diameter (or greatest cross-sectionaldimension) that is larger than the diameter (or greatest cross-sectionaldimension) of the elongate portion 162 and 164 of the prongs proximal tothe distal portions. This may allow a portion of the distal portions 176and/or 178 (e.g., the electrodes, described below) to be brought intocontact with a subject's tissue, while the elongate portions 162 and 164are not in contact with the subject's tissue. For example, the diameterof the nasal insertion prongs 106 and 108 at the distal portions 176 and178 may in some instances be between about 3 mm and about 7 mm, whilethe diameter of the elongate portions 162 and 164 may be between about 1mm and about 6 mm proximal to the distal portions. More specifically, insome variations the diameter of the nasal insertion prongs at the distalportions 176 and 178 may be about 5 mm, and the diameter of the elongateportions 162 and 164 may be about 3 mm. The proximal portion of theelongate portions 162 and 164 may flare outward (i.e., have anincreasing diameter or greatest cross-sectional dimension) toward thebase member, which may in some variations act as a stop to limit thedistance that the nasal insertion prongs 106 and 108 may be advancedinto the nose of a user.

The first and second nasal insertion prongs 106 and 108 may be connectedto each other via a base member 126. In the variation shown in FIGS.5A-5F, the prongs 106 and 108 may be integrally formed with the basemember 126 by a rigid support 218 and a flexible overlay 220, as shownin FIG. 5C. The rigid support 218 may provide support to the base of thenasal insertion prongs 106 and 108 and may interface with the top of thestimulator body 102, as described in more detail below. The rigidsupport 218 may comprise any suitable material or materials, such as arigid plastic. For example, in some variations, the rigid support 218may comprise a thermoplastic such as acrylonitrile butadiene styrene(ABS), polycarbonate, polyetherimide (e.g., ULTEM™ polyetherimide). Itmay in some instances be desirable for the rigid support 218 to comprisethe same material as a portion of the stimulator body 102 (e.g., theproximal housing 142 (described above)), in order to improve the abilityto attach the stimulator probe 104 to the stimulator body 102, asdescribed in more detail below. In some variations, the rigid support218 may comprise a bottom portion 240 configured to interface with thestimulator body 102, and a top portion comprising one or more supports242 (e.g., as shown in FIG. 5G, three supports 242). The top portion mayfurther comprise two lumens 208 and 210, configured to receive leads asdescribed below. In some variations, the supports 242 may besaddle-shaped.

The flexible overlay 220 may form the nasal insertion prongs 106 and 108and may wrap around the rigid support 218 to form the base member 126.The flexible overlay 220 may comprise any suitable material ormaterials. The flexible overlay 220 may comprise a more flexiblematerial than the rigid support 218. For example, in some variations theflexible overlay 220 may comprise a flexible polymer, such as athermoplastic elastomer (e.g., thermoplastic elastomer alloys (e.g.,VERSAFLEX™ thermoplastic elastomer), thermoplastic polyurethanes, or thelike), silicone, or the like. Although the nasal insertion prongs 106and 108 may be integrally formed with the base member 126 in stimulatorprobe 104, in other variations, the nasal insertion prongs mayseparately formed from the base member.

The base member 126 may allow the nasal insertion prongs 106 and 108 tobe manipulated as a single unit (and disposed as a single unit, ininstances where the stimulator probe is disposable). In some variations,the base member 126 may act as a stop to limit the distance that thenasal insertion prongs 106 and 108 may be advanced into the nose of auser. Additionally or alternatively, one or more of the nasal insertionprongs may include a flange or other mechanical stop to limit thedistance that the prongs may be inserted into a user's nose. The basemember 126 may further help to control the relative orientation of theprongs. For example, as shown in FIGS. 5A-5F, the two nasal insertionprongs 106 and 108 may be connected to the base member 126 such that thetwo prongs are oriented substantially parallel to each other. In somevariations, having the nasal insertion prongs oriented substantiallyparallel to each other may provide advantages in manufacturing and mayaid in nasal insertion. However, in other variations, the nasalinsertion prongs may not be oriented parallel to each other. Forexample, in some variations, the nasal insertion prongs may be angledtoward each other.

The two nasal insertion prongs may be positioned with any suitabledistance between them (e.g., between about 3 mm and about 15 mm). Insome variations, it may be desirable for the distance between the twonasal insertion prongs to be such that they fit simultaneously into eachof the user's nostrils on either side of the septum. Additionally oralternatively, it may be desirable for the distance to be such that thenasal insertion prongs are configured to self-align to the desiredstimulation location (described in more detail below) when inserted intothe user's nasal cavities. In some of these variations, the distancebetween the central longitudinal axes of the two nasal insertion prongs106 and 108 (labeled as distance “A” in FIG. 5A) may be between about 12mm and about 16 mm. The diameter of the nasal insertion prongs at thedistal portions 176 and 178 may in some instances be about 3 mm to about7 mm as described above, and thus the distance between the distalportions (labeled as distance “B” in FIG. 5A) may be about 5 mm to about11 mm. More specifically, in some variations the distance between thecentral axes of the two nasal insertion prongs 106 and 108 may be about14 mm, and the diameter of the nasal insertion prongs at the distalportions 176 and 178 may be about 5 mm, and thus the distance betweenthe distal portions may be about 11 mm.

The one or more nasal insertion prongs may have any suitable length. Insome variations, the length of the one or more nasal insertion prongsmay be such that when inserted into the nasal cavity, at least a portion(e.g., distal portions 176 and 178) is capable of reaching the area ofthe nasal cavity that is desired to be stimulated. For example, thelength of the one or more nasal insertion prongs may be such that wheninserted into the nasal cavity, at least a portion is capable ofreaching the nasal mucosa or other area desired to be stimulated, asdescribed in more detail below. In some variations, the length of theone or more nasal insertion prongs extending from the base member (i.e.,the farthest the nasal insertion prongs could be inserted into the nasalcavity) may be between about 25 mm and about 45 mm. In other variations,the length of the one or more nasal insertion prongs extending from thebase member may be between about 30 mm and about 40 mm. For example, insome variations, such as variations in which the stimulation targetincludes the anterior ethmoidal nerve, the nasal insertion prongs 106and 108 may have a length extending from the base member 126 of about37.5 mm (labeled as distance “C” in FIG. 5A). As another example, whenthe stimulation target includes an internal branch of the infraorbitalnerve, the length of the one or more nasal insertion prongs extendingfrom the base member may be between about 8 mm and about 20 mm. As yetanother example, when the stimulation target includes a superior branchof the greater palatine nerve, the length of the one or more nasalinsertion prongs extending from the base member may be between about 20mm and about 40 mm. As yet another example, when the stimulation targetincludes a posterior superior lateral nasal branch of the maxillarynerve (when the tissue to be stimulation includes the middle and/orsuperior turbinates), the length of the one or more nasal insertionprongs extending from the base member may be between about 20 mm and 60mm (e.g., between about 25 mm and about 35 mm, between about 30 mm andabout 40 mm, between about 25 mm and about 40 mm). In other variationsthe nasal insertion prongs may be different lengths and/or adjustablelengths, and additionally or alternative may comprise one or more bendsor curves.

The nasal insertion prong dimensions and configuration described withrespect to stimulator probe 104 may allow the nasal insertion prongs 106and 108 to self-align to the desired stimulation location when insertedinto a user's nasal cavities. The length of the nasal insertion prongsis desirably long enough such that the prongs can reach the desiredstimulation location (e.g., the nasal mucosa superior to the columella,such as near the interface between the nasal bone and the upper lateralcartilage; tissue innervated by a nerve target, such as but not limitedto the anterior ethmoidal nerve, internal branches of the infraorbitalnerve, superior branches of the greater palatine nerve, septal nerve, orposterior superior lateral nasal branch of the maxillary nerve) in arange of patients. However, it should be appreciated that in someinstances it may be desirable to stimulate the columella. For thosepatients having a larger distance between the columella and the desiredstimulation location, a longer portion of the nasal insertion prongs maybe inserted into the nasal cavities. For those patients having a shorterdistance between the columella and the desired stimulation location, ashorter portion of the nasal insertion prongs may be inserted into thenasal cavities. Because the patient's nasal cavities may narrow frominferior to superior, as the nasal stimulation prongs are advancedsuperiorly into the nasal cavities toward the desired stimulationlocation, the nasal tissue may generate a force pressing the nasalinsertion prongs medially. When the nasal insertion prongs comprise aflexible material (e.g., a flexible polymer, such as a thermoplasticelastomer (e.g., a thermoplastic elastomer alloy (e.g., VERSAFLEX™thermoplastic elastomer), thermoplastic polyurethane, or the like),silicone, or the like) as described herein, the nasal insertion prongsmay flex medially, bringing them into contact with the desiredstimulation location.

In some variations, it may be desirable to have a particular flexibilityor range of flexibilities in order to allow the nasal insertion prongsto self-align to the desired stimulation location when inserted into auser's nasal cavities. In these variations, properties of the nasalinsertion prongs (e.g., the Young's modulus, thickness of the flexiblematerial or materials, the properties of the leads located within theprongs (described in more detail herein)) may be chosen to allowself-alignment. Generally, it may be desirable for the prongs to bestiff enough such that they can be pushed into the nasal cavitieswithout buckling, while being flexible enough to self-align and/or to beatraumatic to the nasal tissue during regular use and insertion, and/orduring a sudden movement (e.g., a sneeze). This may also improve comfortfor the user. In some variations, the desired hardness of the materialmay be between about 40 D and about 90 D, between about 50 D and about80 D, between about 60 D and about 70 D, or about 65 D. In addition tohaving material properties that may be atraumatic to nasal tissue, itmay be desirable for the distal tips of the nasal insertion prongs tohave rounded edges to help minimize the risk of tissue damage duringadvancement of the prongs into the nose.

When the stimulators described here are configured to deliver anelectrical stimulus, at least one of the nasal insertion prongs maycomprise one or more electrodes configured to deliver a stimulus totissue. In variations where a stimulator comprises two nasal insertionprongs, each of the two nasal insertion prongs may comprise at least oneelectrode. Having multiple electrode-bearing prongs may allow thestimulator to provide bipolar stimulation (and/or bilateral stimulationof two nostrils), as discussed in more detail herein.

When a nasal insertion prong or prongs of the stimulators describe herecomprise one or more electrodes, the electrodes may have any suitabledesign. In variations in which the electrodes comprise an arc of acylindrical surface, such as in the variation shown in FIGS. 5A-5F, theelectrodes 110 and 112 may comprise about a 100 degree arc of acylindrical surface. That is, openings 180 and 182 in the distalportions 176 and 178 of the nasal insertion prongs may comprise about a100 degree arc of a cylinder, and the electrodes 110 and 112 may belocated within the openings 180 and 182. In other variations, theelectrodes may be any suitable arc length of a cylinder and further mayhave any suitable shape. For example, in some variations the electrodesmay comprise a complete cylinder (e.g., may extend 360 degrees aroundthe distal portions of the nasal insertion prongs), or in othervariations, the electrodes may have a domed shape that includes thedistal tips of the nasal insertion prongs. Such a complete cylinder ordomed shape may be desirable, for example, when the targeted tissue areacomprises two or more areas of tissue (e.g., stimulation is configuredto stimulate two or more target nerves simultaneously). For example,such electrodes may be desirable when the targeted tissue areas comprisethe area innervated by the superior branches of the greater palatinenerve and the area innervated by the nasopalatine nerve. As anotherexample, such electrodes may be desirable when the targeted tissue areascomprise the area innervated by the posterior superior lateral nasalbranches of the maxillary nerve and the area innervated by thenasopalatine nerve.

When the nasal insertion prongs comprise one or more electrodes, thecenter of the electrodes may be angled relative to the axis intersectingthe first and second prongs. In some variations, the electrodes may beangled such that when the first nasal insertion prong is positioned in afirst nostril and the second nasal insertion prong is positioned in thesecond nostril, the electrodes may be directed toward the front of thenose. When an electrical stimulus is delivered through the electrodes ofthe first and second nasal insertion prongs, the stimulation energy maybe directed toward the front of the nose. This may allow for selectiveactivation of nerves in the front of the septum and nasal mucosa, whileminimizing activation of nerves toward the rear of the nasal septum.This may reduce negative side effects that may occur from stimulation ofnerves that innervate the teeth. Specifically, in the variation of thestimulator probe 104, as shown in FIG. 5D, the center of the electrode110 of the first nasal insertion prong 106 (shown by line 226) may berotated at an angle θ₁ relative to the axis 166 intersecting the first106 and second 108 nasal insertion prongs, while the center of theelectrode 112 of the second nasal insertion prong 108 (shown by line228) may be rotated at an angle θ₂ relative to the axis 166.

The angles θ₁ and θ₂ of the stimulator probe 104 may be the same ordifferent, and may be any suitable value (e.g., about 45 degrees, about90 degrees, about 180 degrees, between about 0 degrees and about 90degrees, between about 15 and about 75 degrees, or the like). In somevariations, it may be desirable for angles θ₁ and θ₂ to be greater thanabout 10 degrees. In other variations, the center of the electrodes mayface each other (e.g., angles θ₁ and θ₂ may be zero). This may cause theelectrodes to face toward septal tissue when each nasal insertion prongis positioned in a nostril. In some variations, this may enhanceactivation of rhinorrhea and/or may enhance constriction of the laminapropia. In other variations, the centers of the electrodes may face inthe same direction or nearly in the same direction (e.g., angles θ₁ andθ₂ may be between about 70 degrees and about 90 degrees, which may causethe electrodes to face toward the front of the nose when each nasalinsertion prong is positioned in a nostril). In other variations, thecenters of the electrodes may be oriented such that angles θ₁ and θ₂ maybe between about 10 degrees and about 50 degrees. In yet othervariations, the centers of the electrodes may be oriented such that theelectrodes face away from each other. In some instances, this may allowfor stimulation of tissue in the nasal turbinates and/or tissueinnervated by the superior branches of the greater palatine nerve. Inthe variation shown in FIG. 5D, the angles θ₁ and θ₂ may each be 45degrees. As such, when the stimulator probe 104 or 1200 is positionedsuch that the first nasal insertion prong is positioned in a firstnostril and the second nasal insertion prong is positioned in the secondnostril, the electrodes may be directed partially toward the front ofthe nose. For example, FIG. 6 shows electrodes 608 positioned innostrils 620 against septum 622 and directed partially toward the frontof the nose.

The electrodes may be positioned on any suitable longitudinal portion orportions of the nasal insertion prongs. The position of the electrodealong the prong may at least partially determine the placement of theelectrode relative to tissue when the stimulator probe is advanced intothe nose. In some variations, an electrode may be located at anintermediate position along a prong of stimulator. For example, in thevariation of the stimulator probes depicted in FIGS. 5A-5F, theelectrodes 110 and 112 may be located at an intermediate position alongthe nasal insertion prongs, within the distal portions 176 and 178 theprongs but not at the distal tip of the prongs. The electrodes 110 and112 may be located any suitable distance from the distal tip of theprongs, such as between about 0.1 mm and about 4 mm, about 4 mm andabout 8 mm, or more than 8 mm from the distal dip of the prongs (e.g., 1cm from the distal tip). In some variations, the electrodes 110 and 112may be located about 2.5 mm from the distal tip of the prongs. In somevariations, the electrodes may be locate such that when inserted intothe nasal cavity, the electrodes are capable of reaching the nasalmucosa or other area desired to be stimulated. In some variations,distance from the base member of the stimulator probe to thelongitudinal center of the electrode (i.e., the farthest the center ofthe electrode could be inserted into the nasal cavity) may be betweenabout 25 mm and about 45 mm. In other variations, the distance from thebase member of the stimulator probe to the longitudinal center of theelectrode may be between about 30 mm and about 40 mm. For example, insome variations the distance from the base member of the stimulatorprobe to the longitudinal center of the electrode may be about 32.5 mm(labeled as distance “D” in FIG. 5A). In other variations, the distancefrom the base member of the stimulator probe to the longitudinal centerof the electrode may be between about 20 mm and about 60 mm (e.g.,between about 25 mm and about 35 mm, between about 30 mm and about 40mm, between about 25 mm and about 45 mm, between about 20 mm and about40 mm). In other variations, the distance from the base member of thestimulator probe to the longitudinal center of the electrode may bebetween about 8 mm and about 20 mm. The electrode may have any suitablelength, such as between about 1 mm and about 10 mm, between about 3 mmand about 7 mm, about 5 mm, or more than about 10 mm.

The electrode(s) described here may be made from one or more conductivematerials. In some variations, the electrodes may comprise metals (e.g.,stainless steel, titanium, tantalum, platinum or platinum-iridium, otheralloys thereof, or the like), conductive ceramics (e.g., titaniumnitride), liquids, gels, or the like. In some variations, the electrodemay comprise one or more materials configured to promote electricalcontact between electrodes of the stimulator probe and tissue (i.e., allof an electrodes or a portion of the electrode, such as a covering). Insome instances, the impedance provided by tissue may be at leastpartially dependent on the presence or absence of fluid-like materials(e.g., mucous) in the nasal cavity. The material(s) may help to minimizethe impact of subject tissue impedance by providing a wet interfacebetween the electrode and tissue, which may act to normalize theimpedance experienced by the electrodes. This may in turn normalize theoutput and sensation experienced by the user.

In the variation shown in FIGS. 5A-5F, the electrode may comprise ahydrogel. The hydrogel may be any suitable hydrogel, including thehydrogels described in U.S. patent application Ser. No. 14/630,471,filed on Feb. 24, 2015, and titled “POLYMER FORMULATIONS FORNASOLACRIMAL STIMULATION,” which is hereby incorporated by reference inits entirety. The hydrogel may be located within the openings 180 and182 of the distal portions 176 and 178 of the nasal insertion prongs 106and 108. The hydrogel electrode may form about a 100 degree arc of acylinder, although it should be appreciated that the hydrogel electrodemay in other variations have other shapes (e.g., a smaller or largerarc, as described in detail herein). The hydrogel may fill the openings180 and 182 and the adjacent portions of the central lumens 222 and 224of the nasal insertion prongs. As such, the hydrogel may surround theaxial portion of the leads located adjacent to the openings 180 and 182.In some variations, the distal portions 176 and 178 of the nasalinsertion prongs may further be covered by a thin hydrogel skin. Thehydrogel skin may help to retain the hydrogel electrodes within thedistal portions 176 and 178 of the nasal insertion prongs 106 and 108.Additionally or alternatively, in variations having a hydrogel skin, thehydrogel skin may improve manufacturability (e.g., by allowing theelectrodes to be formed by dip coating). In some variations, the distalportions 176 and 178 of the nasal insertion prongs 106 and 108 maycomprise retention columns located between the surface of the electrodeand the central lumens 222 and 224. The retention columns may help toretain the leads within the central lumens, and when the electrodescomprise a hydrogel, may help to retain the hydrogel within the opening180 and 182.

When a nasal insertion prong or prongs of the stimulators described herecomprise one or more electrodes, the electrodes may comprise leads. Whenthe stimulator probe is connected to a stimulator body, the leads maycontact the circuitry of the stimulator body to electrically connect theelectrodes to the stimulator body circuitry, as described in more detailherein. As such, the leads may extend at least partially through each ofthe nasal insertion prongs. The leads may be formed from one or moreconductive materials (e.g., stainless steel, titanium, platinum orplatinum-iridium, other alloys thereof, or the like), conductiveceramics (e.g., titanium nitride), and may be positioned such that atleast a portion of each lead contacts a respective electrode to providea conduction pathway between the lead and the electrode.

The leads of stimulator probe 104 can be seen in the cut-away view inFIG. 5C. As shown there, the leads 130 and 132 may each comprise aspring. The springs comprising leads 130 and 132 may comprise anysuitable biocompatible conductive material or materials. For example, insome variations, the springs may comprise stainless steel. In othervariations, the springs may comprise gold or platinum. In somevariations, the springs may comprise two or more materials (e.g.,stainless steel with gold plating). The leads 130 and 132 may extendthrough the central lumens 222 and 224 of the nasal insertion prongs 106and 108, respectively. A portion of the leads (e.g., the distal ends)may contact the electrodes. For example, distal ends of the leads 130and 132 may extend through the hydrogel forming electrodes 110 and 112,as described in more detail herein. In variations in which the leadscomprise springs, the wound coil of the springs may allow for a greaterconductive surface between the leads and the hydrogel electrode ascompared to a single straight wire. Additionally or alternatively, thewound coil of the springs 130 and 132 may grip the hydrogel electrode,thus better retaining it within the distal portions 176 and 178 of thenasal insertion prongs 106 and 108. The proximal ends of the leads 130and 132 may extend through the lumens 208 and 210 through the rigidsupport 218, such that the proximal ends of the leads are able tocontact the circuitry of the stimulator body, as described in moredetail herein. In variations in which the leads comprise springs, theproximal ends 184 and 186 of the springs may have a tighter pitch thanthe rest of the springs. This may create a more even surface to contactthe circuitry of the stimulator body. The spring force may also promotecontact between the leads and the circuitry of the stimulator body, asdescribed in more detail herein. Additionally or alternatively, theproximal ends 184 and 186 may have a different (e.g., greater) coildiameter than the rest of the springs, which may also improve thecontact between the leads and a portion of the stimulator body. Itshould be appreciated the leads need not comprise springs. In othervariations, for example, stimulator probes may comprise leads comprisinga conductive loop.

Generally, when the stimulator probes described here are configured todeliver an electrical stimulus, the external surfaces of any of thestimulator probes described herein may be insulated, with the exceptionof the electrodes. This may help to prevent inadvertent stimulation ofother tissue (e.g., by direct tissue contact with a lead instead of withan electrode). Accordingly, in some variations, the prongs may be formedfrom or otherwise coated with one or more insulating materials (e.g.,PTFE, silicone, combinations thereof, or the like). For example, in thevariation of the stimulator probe shown in FIGS. 5A-5F, the first andsecond prongs may be formed from an insulating material such as aflexible polymer (e.g., a thermoplastic elastomer (e.g., thermoplasticelastomer alloys (e.g., VERSAFLEX™ thermoplastic elastomer),thermoplastic polyurethanes, or the like), silicone, or the like), andthe leads may be positioned inside the prongs such that they areelectrically insulated from the exterior surfaces of the first andsecond prongs during use of the stimulator probe, as described herein.Accordingly, in these instances, electrical stimulation energy providedto the leads may be delivered via the electrodes.

Other variations and features of stimulator probes and componentsthereof are described in U.S. application Ser. No. 14/256,915, filedApr. 18, 2014, and titled “NASAL STIMULATION DEVICES AND METHODS,” whichwas previously incorporated by reference in its entirety. For example,while the stimulator probes in the figures described herein are shown ashaving two nasal stimulation prongs, it should be appreciated that inother variations the stimulator probe may have any suitable number ofprongs (e.g., one, two, or three or more prongs). Similarly, thestimulators may comprise any suitable number of electrodes (e.g., one,two, three, or four or more electrodes), and the electrodes may bepositioned on any suitable portion of the stimulator (e.g., thestimulator body and/or a stimulator probe).

Connection Between Stimulator Body & Probe

The stimulator probes described here (and any prongs thereof) may beconnected to a stimulator body in any suitable manner. In somevariations, a stimulator probe may be configured to directly connect toa stimulator body. In these variations, at least a portion of thestimulator probe may have a fixed location and orientation with respectto the stimulator body when the two are connected. In some of thesevariations, the stimulator probe may be permanently connected to thestimulator body. For example, the stimulator probe and stimulator bodymay be formed together such that they are permanently connected. Inother variations, the stimulator probe may clip, latch, snap onto, orotherwise mechanically connect to the stimulator body. In some of thesevariations, the stimulator probe may be releasably connected to thestimulator body, such that the stimulator probe may be disconnected fromthe stimulator body after being connected.

For example, stimulator body 102 and stimulator probe 104 of stimulator100 may be removably connected such that a portion of the stimulatorprobe 104 directly contacts and connects to the stimulator body 104.FIG. 7 depicts a perspective view of the stimulator 100 showing theconnection mechanism. As shown there, the distal portion 206 of the tophousing 142 of the stimulator body 102 and the proximal portion of thestimulator probe 104 may comprise corresponding and complementaryshapes, which may allow the stimulator body 102 and stimulator probe 104to be attached. For example, the distal portion 206 of the top housing142 of the stimulator body and the proximal surface of the rigid support218 of the stimulator probe 104 may comprise features that allow them tobe reversibly attached. For example, in the variation shown the distalportion 206 of the top housing 142 of the stimulator body 102 maycomprise two notches 192 on a first side and two notches 194 on a secondside. The proximal surface of the rigid support 218 of stimulator probe104 may comprise four corresponding tabs: two tabs 196 on a first sideand two tabs 198 on a second side (shown in FIG. 5E). The stimulatorbody 102 and stimulator probe 104 may be snapped together by firstplacing tabs 198 of the stimulator probe 104 into the notches 194 ofstimulator body 102, and then manipulating the probe 104 and body 102such that the first side of the simulator body 102 is rotated toward thefirst side of the stimulator probe 104. In doing so, the tabs 196 of thestimulator probe 104 may be rotatably inserted into the notches 192 ofthe stimulator body 102. The tabs 196 and 198 and notches 192 and 194may have increased height and depth, respectively, at their proximalends, such that the probe 104 and body 102 are held together by the tabsand notches when connected.

Conversely, the stimulator probe 104 may be removed from the stimulatorbody 102 by rotating the first side of the probe 104 and first side ofthe body 102 away from each other. It may be desirable for thestimulator to be configured such that when a user inserts the stimulatorprobe 104 into his/her nasal cavities, if the user presses a portion ofthe stimulator prongs (e.g., the electrodes) against tissue (e.g.,tissue near the front of the nose), the force on the stimulator probereinforces the connection between the stimulator probe 104 and thestimulator body 102. That is, the force from the user's tissue maydesirably tend to push the first side of the stimulator body 102 towardthe first side of the stimulator probe 104. If, instead, the forcetended to push the first side of the probe 104 and the first side of thebody 102 away from each other, there could be an increased risk of theprobe being inadvertently disconnected from the stimulator body duringstimulation. In some variations, as described in more detail below, thestimulator probe 104 may further comprise tab 200 configured to fit intonotch 202 of stimulator body 102, which may help the control subsystem136 to register the connection of the stimulator probe 104 to thestimulator body 102.

It should be appreciated that in other variations, the stimulator bodyand stimulator probe may have any suitable features for being attached,such as other snapping mechanisms (e.g., having different shapes ordifferent numbers of features), magnets, friction fits, a latchingmechanism, or the like. For example, in some variations the stimulatorbody may comprise a magnet (e.g., magnet 134 of stimulator body 102)connected to the interior surface of the proximal housing of thestimulator body. The stimulator probe may comprise a magnet orferromagnetic material in a corresponding location (e.g., in the basemember of the stimulator probe), which may retain the stimulator probeon the stimulator body.

Generally, when the stimulators described here are configured to deliveran electrical stimulus, the electrodes of the stimulator may beelectrically connected to the stimulator circuitry, such that thestimulator may generate a stimulus and deliver it to tissue via one ormore of the electrodes. Accordingly, the stimulators described here maycomprise one or more electrical connections configured to electricallyconnect the electrode via a lead to a portion of the stimulator body(e.g., a stimulation subsystem housed in the stimulator body). Invariations in which the stimulator probe and stimulator body areindirectly connected, the indirect connection (e.g., a cable, cord, orthe like) may serve as the electrical connection between the stimulatorcircuitry and the electrodes. In variations in which the stimulatorprobe and the stimulator body are directly connected, the stimulatorbody and stimulator probe may comprise conductive elements configured toelectrically connect the electrodes of the stimulator probe to thestimulator circuitry when the body and probe are connected.

For example, as shown in FIG. 1D, the electrodes 110 and 112 ofstimulator probe 104 may be connected to leads 130 and 132 locatedwithin nasal insertion prongs 106 and 108, respectively. Thecorresponding stimulator body 102 may comprise connectors 122 and 124directly or indirectly connected to the control subsystem 136 and powersource 152. The distal ends of the connectors 122 and 124 may beconfigured to connect with the proximal ends of the leads 130 and 132 ofthe stimulator probe 104. As shown in FIG. 3A, in some variations thedistal ends of the connectors may comprise a rounded surface. Invariations in which the leads comprise springs, the proximal ends of thesprings may have a tighter pitch than the rest of the springs. This maycreate a more even surface to contact proximal ends of the connectors,and thus may allow for a better electrical connection between the leadsof the stimulator probe 104 and the connectors of the stimulator body102.

When the proximal ends of the springs of stimulator probe 104 are incontact with the connectors 122 and 124 of the stimulator body 102, thesprings may be compressed. This compression may cause the springs togenerating a restoring force. The restoring force may promote contactbetween the springs and the connectors 122 and 124. However, invariations in which the stimulator probe 104 is removably connectable tothe stimulator body 102, the restoring force may also act against theforce of the connection mechanism holding together the stimulator probeand the stimulator body (e.g., notches 192 and 194 and tabs 196 and198). Thus, it may be desirable for the spring stiffness to be lowenough that the restoring force of the springs does not cause thestimulator probe to disconnect from the stimulator body.

The connectors 122 and 124 may extend through lumens 208 and 210 in theproximal housing 142, and the proximal ends may be directly orindirectly attached to the control subsystem. As shown in FIG. 3D, theproximal ends of the connectors 122 and 124 may comprise slotsconfigured to receive the distal ends of contact strips 244. Theproximal ends of contact strips 244 may be attached to the controlsubsystem 136 (i.e., may be attached to the printed circuit board 128).The connectors and contact strips may comprise any suitable conductivematerial or materials, such as but not limited to stainless steel,titanium, copper, nickel, brass, zinc, or the like, which may in someinstances be gold-plated.

It should be appreciated that the stimulator body and stimulator probemay additionally or alternatively be inductively coupled, such thatpower may be transferred from the stimulator body to the stimulatorprobe via induction. In these variations, the stimulator body andstimulator probe may each comprise a coil. In some variations, each ofthe coils may be wrapped around a ferromagnetic (e.g., iron) core, butneed not be. In some variations, the coil of the stimulator body and/orstimulator probe may be a printed coil.

Other variations and mechanisms for physical and electrical connectionbetween the stimulator body and stimulator probe are described in U.S.application Ser. No. 14/256,915, filed Apr. 18, 2014, and titled “NASALSTIMULATION DEVICES AND METHODS,” which was previously incorporated byreference in its entirety.

In some variations, some or all of the stimulator may be disposable. Invariations where the stimulator body is permanently attached to thestimulator probe, the entire stimulator may be disposable. In othervariations, one or more portions of the stimulator may be reusable. Forexample, in variations where the stimulator probe is releasablyconnected to the stimulator body, the stimulator body may be reusable,and the stimulator probe may be disposable. As such, the stimulatorprobe may be periodically replaced. In yet other variations, a portionof the stimulator probe may be disposable (e.g., the stimulator probemay comprise disposable sleeves or disposable prongs) and may beperiodically replaced. In some variations, the stimulators describedhere may comprise features that encourage or require a user to replace astimulator or stimulator components after a certain period or on aregular basis in order to main proper hygiene.

In variations in which the entire stimulator is disposable (e.g., whenthe stimulator probe is integrally formed with or permanently attachedto the stimulator body), the stimulator may be configured to becomenon-operational after a certain period of time and/or use. In some ofthese variations, the stimulator may be configured to limit the durationof stimulation that may be provided by the stimulator; after theduration limit, the stimulator may be configured to becomenon-operational. For example, the stimulator may have a power sourcethat is only sufficient to power stimulus delivery for a predeterminedduration (e.g., one hour of stimulation). Once the power source has beendepleted, a user may need to replace the spent stimulator with a newstimulator. In some of these variations, the stimulator may beconfigured such that the power source cannot be accessed withoutrendering the device inoperable, which may help prevent users fromreplacing the power source.

As another example, the stimulator additionally or alternatively may beprogrammed to limit the duration or amount of stimulus delivery with agiven stimulator. In some of these variations, the stimulator may beconfigured to measure and store the duration of stimulation provided bythe stimulator over time (which may be cumulatively added over aplurality of different treatment sessions). When the duration reaches athreshold limit (e.g., about 10 minutes, about 30 minutes, about onehour, about 2 hours, or longer than 2 hours), the stimulator may beprogrammed to switch to an inoperable state, whereby the stimulator maynot be activated to provide additional stimulation. As another example,the stimulator additionally or alternatively may be configured to limitthe number of treatment sessions provided by the stimulator. In some ofthese variations, the stimulator may be configured to measure and storethe number of treatment sessions provided by the stimulator. When thenumber of treatment sessions reaches a threshold limit (e.g., five uses,ten uses, fifteen uses, or more than fifteen uses), the stimulator maybe programmed to switch to an inoperable state, whereby the stimulatormay not be activated to provide additional stimulation.

In these or other variations in which the entire stimulator isdisposable, the stimulator may additionally or alternatively beconfigured to become non-operational after a certain period of timeafter its first use. The stimulator may be configured to limit theduration since the first use of the stimulator; after the durationlimit, the stimulator may be configured to become non-operational. Insome of these variations, the stimulator may be configured to store dateand time information regarding the first use of the stimulator. Thestimulator may be further configured to switch to an inoperable statewhen a predetermined amount of time (e.g., one day, two days, five days,one week, two weeks, or longer than two weeks) has passed from the firstuse of the stimulator.

In any of these variations, the stimulator may be configured to limitthe duration of stimulus delivery, the number of treatment sessions, orthe duration since first use via a control subsystem, which may in someinstances comprise intelligence such as a microcontroller, programmablelogic (e.g., a field-programmable gate array), or anapplication-specific integrated circuit (ASIC) configured to measure,store, and limit the duration and/or number of treatment sessions and/orthe time since first use of the stimulator. In any of these variations,when the device moves to an inoperable state, the user may need toreplace the inoperable stimulator with a new stimulator.

In variations in which the stimulator body is reusable and all or aportion of the stimulator probe is disposable, the stimulator may beconfigured to encourage and/or require the user to replace all or aportion of the stimulator probe. In some of these variations, thedisposable portion probe or portion of the probe may comprise arecyclable material. In some of these variations, the stimulator may beconfigured such that the stimulator probe or a portion thereof becomesinoperable after being attached to the stimulator body for apredetermined amount of time (e.g., between about 1 hour and about 24hours, between about 1 day and about 7 days, between about 1 week andabout 4 weeks, between about 1 month and about 3 months, or longer thanabout 3 months), after a predetermined number of treatment sessions,and/or after a predetermined duration of stimulation (e.g., betweenabout 2 minutes and about 30 minutes, between about 30 minutes and about1 hour, between about 1 hour and about 3 hours, between about 3 hoursand 12 hours, or longer than about 12 hours).

For example, in some variations of stimulators comprising one or moreelectrodes, the electrodes of the stimulator probe may become inoperableafter being attached to the stimulator body for a predetermined amountof time, after a predetermined number of treatment sessions, and/orafter a predetermined duration of stimulation. For example, in somevariations it may be desirable to promote oxidation of one or more ofthe electrodes during stimulation. In these variations, the electrodemay be configured to form a non-conductive (or reduced conductivity)layer on the surface of the electrode. In some variations, this mayinterfere with the ability of the electrode to stimulate tissue, andeventually the oxide layer may substantially prevent any electricalenergy from being supplied to the user. In some instances, to form sucha layer, the stimulator may be configured to deliver biphasic pulsesusing the electrodes, wherein the biphasic pulses are notcharge-balanced. By not charge-balancing the stimulation pulses, chargemay accumulate on one or more of the electrodes and/or leads, which mayfacilitate oxidation of the metal of the electrode and/or lead. The rateof the oxidation may be controlled at least partially by the materialsof the electrode and/or lead and the parameters of the pulses deliveredby stimulator, and the rate of oxidation may be tailored to achieve apredetermined treatment duration or number of treatment sessions beforeformation of an oxide layer may render the stimulator inoperable. Asanother example, in some variations, an electrode of a stimulator probeadditionally or alternatively may be configured to change color overtime (e.g., as a result of delivering stimulation, as a result of carbondioxide exposure, as a result of oxidation), such that a user may beprompted to change the stimulator probe when the electrode reaches acertain color. In these variations, the stimulator probe or a portion ofthe stimulator probe (e.g., nasal insertion prongs or sleeves comprisingthe electrodes) may be replaced when the electrodes of the stimulatorprobe are unable to provide stimulation or when the stimulatorencourages replacement via the color change.

As yet another example, in some variations the stimulator may beprogrammed to render the stimulator probe inoperable and/or to encouragereplacement of the stimulator probe or a portion thereof (e.g.,disposable prongs or sleeves) after being attached to the stimulatorbody for a predetermined amount of time, after a predetermined number oftreatment sessions, and/or after a predetermined duration ofstimulation. In some of these variations, the stimulator may beprogrammed to measure the duration of stimulation provided using aspecific stimulator probe or portion thereof, the number of treatmentsessions provided using a specific stimulator probe or portion thereof,and/or the duration of attachment of a specific stimulator probe orportion thereof to the stimulator, via mechanisms described in moredetail herein. In variations where the stimulator is programmed tomeasure multiple of the above-listed parameters, if the measurementreaches a threshold value, the stimulator may be configured to alert theuser and/or to enter an inoperable state until the current stimulatorprobe or portion thereof is replaced. In variations where the stimulatoris programmed to measure multiple of the above-listed parameters, thestimulator may be configured to alert the user and/or enter theinoperable state when any of the measured parameters reaches itsthreshold value, or the stimulator may require multiple of the measuredparameters to reach their corresponding threshold values in order toalert the user and/or enter an inoperable state. The stimulator mayalert the user in any suitable manner, including visual feedback (e.g.,generating a prompt on a display, activating a LED, notifying the useron another device, such as a computer or mobile device, or the like),audio feedback (e.g., generating one or more beeps or audio prompts),and/or tactile feedback (e.g., vibrating the stimulator). Similarly, invariations in which the stimulator has entered its inoperable state, thestimulator may additionally or alternatively be configured to instructthe user to replace the stimulator probe. This may also be done in anysuitable manner, including visual, audio, or tactile feedback.

Additionally or alternatively, in some variations the stimulator may beconfigured to alert the user and/or enter an inoperable state when aused stimulator probe is attached to the stimulator body. The stimulatormay alert the user in any suitable manner, and may additionally oralternatively be configured to instruct the user to replace thestimulator probe, as described herein. In these variations, thestimulators may comprise a mechanism for determining whether theattached stimulator probe is new (i.e., whether the stimulator probe hasbeen previously attached to a stimulator body or not). In somevariations, the mechanism for determining whether the stimulator probeis new may comprise a fuse. In some variations, the fuse may temporarilyshort circuit the stimulator circuitry while the probe is beingconnected to the stimulator body.

One or more mechanisms for determining when a stimulator probe isattached may also be used in some variations to render the stimulatorprobe inoperable and/or to encourage replacement of the stimulator probeor a portion thereof (e.g., disposable prongs or sleeves) after apredetermined number of treatment sessions, and/or after a predeterminedduration of stimulation. In some of these variations, attachment of thestimulator probe may be registered using one or more of thesemechanisms, and the stimulator may be programmed to measure the durationof stimulation or number of treatment sessions provided using thatstimulator probe. The stimulator may be configured to do so viaintelligence in a control subsystem, such as a microcontroller,programmable logic (e.g., a field-programmable gate array), or anapplication-specific integrated circuit (ASIC).

In some variations, the stimulators described here may be configuredsuch that it may be necessary to replace a disposable stimulator probein order to recharge the stimulator or to replace a power supply of thestimulator. For example, in some variations where the stimulatorcomprises one or more electrical contacts or ports configured to connectto an external power source, the stimulator probe may be configured tocover or otherwise block access to the electrical contacts/ports whenthe stimulator probe is connected to the stimulator body. In thesevariations, it may be necessary to remove the stimulator probe toprovide access to the electrical contacts/ports (which may in somevariations disable the stimulator probe, as described in more detailbelow). Similarly, in variations where the stimulator body includes areplaceable power source (e.g., one or more batteries), the stimulatorprobe may block access to the replaceable power source such that thestimulator probe may need to be disconnected from the stimulator bodyprior to replacing the power source.

In variations where a stimulation system comprises a base station (asdescribed in more detail herein), a stimulator may be configured suchthat the stimulator cannot be connected to the base station while astimulator probe is attached to the stimulator body. For example, in thevariations of the stimulation systems shown in FIGS. 10A-10D describedin more detail herein, the base station may comprise a recess sized andconfigured to receive the stimulator body to operationally connect thestimulator body to the base station. Specifically, the recess may besized such that the stimulator body can fit within the recess when thestimulator probe is disconnected from the stimulator body (asillustrated in FIG. 10A), but is prevented from fitting in the recesswhen the stimulator probe is attached to the stimulator body. In thesevariations, it may be necessary to first disengage the stimulator probe.Accordingly, to utilize one or more functions of the base station, auser may need to first decouple a stimulation probe from the stimulatorbody before connecting the stimulator body to the base station. In somevariations, the stimulator probe may comprise a lockout mechanism thatprevents the stimulator probe from being reconnected to the stimulatorbody after being disconnected from the stimulator body. For example, thestimulator may be configured such that the stimulator probe is disabledwhen disengaged from the stimulator body (e.g., when the probe isdisengaged from the stimulator body in order to connect the stimulatorbody to the base station). This may prevent the stimulator probe frombeing reused.

It should be appreciated that any suitable method may be used todetermine whether and for how long a stimulator probe is attached, toalert the user and/or enter an inoperable state when a used stimulatorprobe is attached to the stimulator body, and/or to render thestimulator probe inoperable and/or to encourage replacement of thestimulator probe or a portion thereof, including the methods andmechanisms described in U.S. application Ser. No. 14/256,915, filed Apr.18, 2014, and titled “NASAL STIMULATION DEVICES AND METHODS,” which waspreviously incorporated by reference in its entirety.

Cap & Case

In some variations, the stimulators described here may comprise a cap toprotect the stimulator probe. For example, FIGS. 9A and 9B showperspective and front views, respectively, of stimulator 100 with anattached cap 900. As shown there, the cap 900 may fit over thestimulator probe 104, which may protect the probe from contamination.More particularly, it may be desirable for the cap to protect the nasalinsertion prongs, and especially the electrodes, from contamination. Thecap 900 may have any suitable shape. In some variations, the cap 900 maycover the operating mechanisms when attached to the stimulator. This mayprevent the operating mechanisms from being inadvertently oraccidentally manipulated. As shown in FIGS. 9A-9B, the cap 900 may coverthe buttons 114 and 116 of the stimulator body 102, while leaving thesides of stimulator body 102 exposed. This may allow a user to moreeasily grip the stimulator body 102 in order to remove the cap 900. Insome variations the cap may comprise a texturized surface or othergripping features to assist with removal, such as ridges 904 shown oncap 900. The cap or other enclosure may comprise any suitable materialor materials, such as a plastic or synthetic resin. In some variationsthe cap or other enclosure may be translucent or transparent, while inother variations it may be opaque.

The cap or other enclosure may in some variations comprise one or morefeatures to control the exposure of the stimulator probes to the air.When the probes comprise a hydrogel or other liquid or wet material, theamount of exposure of air may affect the rate at which the hydrogel orother liquid or wet material dries out. For example, in some variationsthe caps may comprise one or more openings to allow for air flowunderneath the cap or other enclosure. Cap 900, for example, maycomprise an opening 902 at the distal end of the cap. In some variationsthe cap may be generally conformed to the shape of the stimulator probe(e.g., by comprising recesses having shapes corresponding to thestimulator prongs' shape and configured to receive the prongs), suchthat the air within the cap is minimal; in other variations, the cap maynot be conformed to the shape of the stimulator probe, such that thereis more air circulating within the cap around the stimulator probe.

In some variations, the cap may comprise one or more features to promoteattachment of the cap to the stimulator body. For example, in somevariations the cap may comprise tabs or bosses, which may be configuredto mate with indentations or cavities on the stimulator. Additionally oralternatively, the stimulator may comprise tabs or bosses, which may beconfigured to mate with indentations or cavities on the cap. In some ofthese variations, the flexibility of the cap material may allow cap tobe placed on the stimulator. Additionally or alternatively, the cap maycomprise one or more living hinges or cutaways 906 and 908, such asshown in FIG. 9C. The living hinges or cutaways may allow the cap toflex in order to slide past a raised feature on the stimulator (e.g., atab or boss); for example, squeezing the top cutaway 906 may cause thebottom portion 908 to rotate away from the stimulator, allowing thebottom portion 908 to slide past a raised feature when attaching orremoving the cap 900. Additionally or alternatively, the cap materialand/or shape may promote attachment of the cap to the stimulator body.For example, the cap may be flexible in order to flex to slide over athicker portion of the stimulator while being attached, and then the capmay relax into a conformal position upon reaching a thinner portion ofthe stimulation.

Other variations and features of caps or enclosures, as well as casesconfigured to hold stimulators, are described in U.S. application Ser.No. 14/256,915, filed Apr. 18, 2014, and titled “NASAL STIMULATIONDEVICES AND METHODS,” which was previously incorporated by reference inits entirety.

Base Station

In some variations, the stimulation systems described here may comprisea base station configured to connect to a portion of the stimulator, thestimulator having a stimulator body and a stimulator probe. The basestation may be configured to releasably connect to one or more portionsof the stimulator, and may be configured to perform one or morefunctions when connected to the stimulator. FIGS. 10A-10D depict aportion of a stimulator system comprising a base station 1000 asdescribed here. FIG. 10A shows a front view the stimulator body 1002docked in the base station 1000, while FIGS. 10B, 10C, and 10D depictside, back, and top views of the base station 1000, respectively. Thestimulator body 1002 and stimulator probe (not shown) may include any ofthe elements of the stimulators described herein. In variations wherethe stimulator body 1002 comprises a rechargeable power source (such asa rechargeable battery, capacitor, or the like), the base station 1000may be configured to recharge the rechargeable power source. Forexample, the base station 1000 may comprise one or more electricalcontacts 1004, which may be configured to electrically connect tocorresponding electrical contacts on the stimulator body 1002. In somevariations, these electrical contacts may be the same electricalcontacts that connect the stimulator probe and the stimulator body(e.g., electrical contacts similar to connectors 122 and 124 ofstimulator 100). This electrical connection may allow the base station1000 to charge the power source of the stimulator body 1002.

In some variations, the base station may comprise a safety mechanismthat prevents power delivery to the electrical contacts unless thestimulator is connected. For example, the base station may comprise asensor configured to detect the stimulator. After the stimulator isdetected, power may be delivered to the contacts. In one variation, thesensor may comprise a magnetic field sensor (e.g., a Hall effectsensor), and the stimulator may comprise a magnet. When the stimulatoris placed in the base station, the magnetic field sensor may detect thepresence of the magnet in the stimulator and may in turn cause power tobe delivered to the contacts.

It should be appreciated that in other variations, the base station mayadditionally or alternatively be configured to inductively charge thestimulator. For example, the base station may comprise a primary coil,which may or may not be wrapped around a ferromagnetic (e.g., iron)core, and the stimulator body may comprise a secondary coil, which mayor may not be wrapped around a ferromagnetic core. When the stimulatorbody is placed in the base station, the coils and iron cores may form acomplete transformer, allowing power to be inductively transferred fromthe base station to the stimulator body. Additionally or alternatively,it should be recognized that inductive power transfer may also be usedto transfer power from the stimulator body to the stimulator probe.

The base station may be powered in any suitable manner. In somevariations, the base station may be connectable to an external powersource (e.g., a wall outlet or separate battery back), which may providepower to the stimulator and/or the base station. In some variations, thebase station may comprise a power cable, which may be permanentlyattached via a strain relief. In other variations, such as the variationof the base station 1000 shown in FIGS. 10A-10D, the base station maycomprise a port 1006 (e.g., a USB port or micro-USB port), which mayconnect the base station 1000 to an external power source. It should beappreciated that the base station 1000 may include any suitable port orconnector for connecting the base station to an external power source.Additionally or alternatively, the base station may comprise a powersource (e.g., one or more batteries) operable to power the base station1000 (and to recharge the stimulator in variations where the stimulatoris rechargeable). The power source may or may not be rechargeable.

The base station 1000 may be configured to rest on a surface (e.g., acounter or table), and may comprise a weight and/or a bottom surfacewith increased friction (e.g., a rubber pad 1008) to help keep the basestation 1000 in place. In variations in which the stimulator comprises amagnet or material attracted to a magnetic field (e.g., iron, nickel,cobalt, alloys thereof and the like), the base station may comprise amagnet in a corresponding location in order to hold the stimulator inplace within the base station. For example, the base station maycomprise a magnet located between the electrical contacts, which may beconfigured to attract a magnet in the stimulator body (e.g., in a basestation configured to receive stimulator body 102, the base station maycomprise a magnet configured to attract the magnet 134 attached to theinterior of proximal housing 142.).

In instances where the stimulator is configured to record or otherwisestore data (e.g., the frequency or duration of stimulation), the basestation may be configured to retrieve data from the stimulator. Forexample, in variations where the stimulator and base station areconfigured to be electrically connected, data may be transmitted viathis electrical connection (e.g., the connection between connectors 122and 124 of stimulator body 102 and electrical contacts 1004 of basestation 1000). FIG. 8 illustrates a schematic diagram of stimulatorcircuitry allowing for the same pins 802 to be used to transfer datafrom the stimulator body to the base station, to transmit a stimulusfrom the stimulator body to the stimulator probe, and to charge arechargeable power source in the stimulator body using the base station.As shown, the pin drivers 804 may take input signals either from a datacommunication subsystem 806 or a stimulation subsystem 808. The input tothe drivers 804 may be determined by a switch 810. In some variations,the switch 810 may comprise a gate, state machine, or amicro-controller. The pins 802 may also be used to charge thestimulator. A rectification circuit 812 may be configured to rectify acharging input signal without interfering with any output stimulation ordata waveform. In some variations, the rectification circuit maycomprise a full wave rectifier comprising rectification diodes, but itshould be appreciated that any suitable circuit may be used. Time blocksfor each function may be synchronized in order for the system to performeach function.

Other variations and features of base stations are described in U.S.application Ser. No. 14/256,915, filed Apr. 18, 2014, and titled “NASALSTIMULATION DEVICES AND METHODS,” which was previously incorporated byreference in its entirety.

In some variations the stimulators described here may be configured toconnect to an external device, such as a mobile device (e.g., a cellulartelephone, a tablet, a wearable computer (e.g., optical head-mounteddisplays such as Google GLASS™ wearable computing device), or the like),a computer, or the like. The stimulators may be configured to connect toan external device through any suitable connection method. In somevariations the connection method may be wireless (e.g., via Wi-Fi,BLUETOOTH™ wireless technology, or the like), and the stimulator maycomprise an antenna or the like. Additionally or alternatively, theconnection method may be via a wired transmission line. In thesevariations, the stimulator may comprise one or more ports (e.g., a USBport), connectors and/or cables configured to physically connect thestimulator to an external device. In some variations, the stimulatorsmay use a wireless or wired connection to connect to the internet, viawhich they may be connected to an external device. In these variations,the device may be at a distant location (e.g., at the manufacturer, at aphysician's office, or the like).

In instances in which the stimulators are configured to connect to anexternal device, the device may be configured to perform one or moreoperations associated with the stimulator. For example, in variationswhere the stimulator is configured to collect data (e.g., one or moresubject parameters, stimulation timing or parameters, stimulatordiagnostic information, such as described in more detail herein) andstore that data in a memory unit of the stimulator, connection of thestimulator to the device may allow for transfer of data stored in thestimulator's memory unit to the device. Specifically, the device andstimulator may be programmed such that upon connection of the device andthe stimulator, the device may download the recorded data stored in thestimulator's memory. In some variations, once data has been transferredfrom the stimulator to the device, the stimulator may be configured todelete this data from the stimulator memory. Because the amount ofmemory available in the device may be greater than that in thestimulator, this transfer may increase the data that may be accumulatedfor a subject.

In addition to or instead of transferring data stored in the stimulatormemory, a device may be configured to collect and store real-time datafrom the stimulator when the two are connected. In some of thesevariations, the stimulator may also be configured to store this data inthe stimulator memory. In some instances, the device may be configuredto transmit data (e.g., via internet connection, cellular data network,or the like) from the device to an external location (e.g., to adatabase where the data may be analyzed, to a physician's office toallow the physician to monitor the data and, in some instances, providefeedback).

In some variations, the device may be configured to solicit input from auser. For example, if the stimulator is used to provide stimulationwhile attached to a device, the device may be configured to solicit theuser to input data regarding the subject's experience (e.g., a subject'slevel of comfort/discomfort, status of subject's symptoms). In somevariations, the device may be configured to present data (and/oranalysis of the data) to a user. For example, the device may beconfigured to display information regarding the frequency ofstimulation, the average duration of stimulation, a graph of subjectcomfort levels over time, or the like. In some variations, the devicemay be configured to share the data or analysis of the data with themanufacturer, clinicians, friends, or others.

It should be appreciated that while certain handheld stimulators havebeen described herein, handheld stimulators for use in the methodsdescribed herein may have any suitable configuration. In addition tothose described herein and in U.S. application Ser. No. 14/256,915,filed Apr. 18, 2014, and titled “NASAL STIMULATION DEVICES AND METHODS,”which was previously incorporated by reference in its entirety,additional handheld stimulators suitable for use in the methodsdescribed herein are described in U.S. patent application Ser. No.14/920,860, filed Oct. 22, 2015, and titled “STIMULATION DEVICES ANDMETHODS FOR TREATING DRY EYE,” which is hereby incorporated by referencein its entirety. Furthermore, while handheld stimulators have beendescribed above, it should be appreciated that in other variations ofthe stimulation systems described here, the stimulation system maycomprise a stimulator configured to be implanted, either permanently ortemporarily, in a subject. It should be appreciated that the implantablestimulators need not be surgically implanted. In some of theseinstances, the implantable stimulator may be configured such that thestimulator may be inserted and/or removed by a user. In others of theseinstances, the implantable stimulator may be configured to be insertedand/or removed by a medical professional. In other instances, thestimulator may be configured to be implanted in or otherwise attached totissue within a nasal or sinus cavity. Variations and features ofimplantable stimulators are described in U.S. application Ser. No.14/256,915, filed Apr. 18, 2014, and titled “NASAL STIMULATION DEVICESAND METHODS,” which was previously incorporated by reference in itsentirety, and in U.S. patent application Ser. No. 14/920,852, filed Oct.22, 2015, and titled “IMPLANTABLE NASAL STIMULATOR SYSTEMS AND METHODS,”which is hereby incorporated by reference in its entirety.

Stimulation Methods

Generally, the stimulators and stimulation systems described herein maybe configured to stimulate nasal or sinus tissue. In some variations,the stimulation may be used to treat allergic rhinitis, non-allergicrhinitis, nasal congestion, ocular allergy, and/or symptoms associatedwith these conditions. Generally, a stimulator (such as described above)may be configured to stimulate trigeminal afferent nerve fibers toactivate the nasolacrimal reflex, which may in turn reduce the symptomsassociated with these conditions. In some of these instances, themethods described herein may comprise stimulating the anterior ethmoidalnerve. In other instances, the methods may comprise stimulating theinternal branches of the infraorbital nerve, the superior branches ofthe greater palatine nerve, the septal nerve, and/or the posteriorsuperior lateral nasal branches of the maxillary nerve.

Location

When an implantable stimulator is used to provide stimulation, theimplantable stimulator may be positioned in a nasal or sinus cavity (ormultiple nasal or sinus cavities). When a handheld stimulator is used toprovide stimulation, one or more prongs of the stimulator may beinserted at least partially into the nose of a user, and a stimulationsignal (such as described herein) may be delivered to the mucosaltissue. A portion of the nasal insertion prong(s) may be positionedand/or manipulated to be placed in contact with any suitable tissue. Invariations in which the stimulators are configured to deliver anelectrical stimulus, the stimulators may be positioned and/ormanipulated to position electrodes into contact with any suitabletissue. FIGS. 4A-4C illustrate certain anatomical locations. Forexample, the nasal insertion prong(s) may be placed in contact with theupper lip 402, external nasal skin 404, nasal ala 406, mucosa of a nasalturbinate (e.g., one or more of the inferior 408, medial 410, orsuperior turbinates 412), or the like. When the stimulators are used totreat nasal congestion, allergic rhinitis, non-allergic rhinitis, ocularallergy, and/or symptoms associated with these conditions, it may insome instances be desirable to position a portion of the nasal insertionprongs (e.g., an electrode) in contact with the nasal mucosa of a nasalturbinate (e.g., a middle and/or superior nasal turbinate). In someinstances, the targeted area may comprise tissue innervated by theanterior ethmoidal branch of the nasociliary nerve, as shown by shadedarea 420 in FIG. 11C. In other instances when the stimulators are usedto treat nasal congestion, allergic rhinitis, non-allergic rhinitis,ocular allergy, and/or symptom associated with these conditions, thetargeted area may comprise tissue innervated by the internal branches ofthe infraorbital nerve; tissue innervated by superior branches of thegreater palatine nerve; tissue innervated by the septal nerve; tissueinnervated by the posterior superior lateral branches of the maxillarynerve; and/or two or more of these areas. In some instances, thetargeted area of the nasal mucosa may be superior to the columella 414.In some of these instances, the targeted area may be near the inferiorend of the nasal bone 416 (i.e., near the interface between the nasalbone 416 and the upper lateral cartilage 418). In other variations, thetargeted area may be the columella. In some variations, it may bedesirable to place a portion of the nasal insertion prong(s) (e.g., anelectrode) between about 20 mm and about 60 mm into the nasal cavity ofthe subject. In some of these variations, it may be desirable to placean electrode between about 20 mm and about 35 mm into the nasal cavityof the subject. In some of these variations, it may be desirable toplace an electrode between about 25 mm and about 35 mm into the nasalcavity of the subject. In some variations, it may be desirable to placean electrode between about 30 mm and 40 mm into the nasal cavity of thesubject. In some variations, it may be desirable to place an electrodebetween about 25 mm and about 40 mm into the nasal cavity of thesubject. In some variations, it may be desirable to place an electrodebetween about 20 mm and about 40 mm into the nasal cavity of thesubject. In some variations, it may be desirable to place and electrodebetween about 8 mm and about 20 mm into the nasal cavity of the subject.In some variations, it may be desirable to place an electrode less thanabout 30 mm into the nasal cavity of the subject, less than about 35 mminto the nasal cavity of the subject, or less than about 40 mm into thenasal cavity of the subject.

As described herein, it may in some instances be desirable to direct thenasal insertion prongs such that a portion (e.g., the electrodes) isdirected toward the front of the nose. This may allow for selectiveactivation of nerves in the front of the septum (e.g., the ophthalmicbranch of the trigeminal nerve) while minimizing activation of nervestoward the rear of the nasal septum, which may reduce negative sideeffects that may occur from stimulation of nerves that innervate theteeth. It may also in some instances be desirable to direct the nasalinsertion prongs so as to reduce negative side effects that may occurfrom stimulation of the olfactory area. In other variations when thestimulators are used to treat nasal congestion, allergic rhinitis,non-allergic rhinitis, ocular allergy, and/or symptoms associated withthese conditions, it may be desirable to direct the nasal insertionprongs such that a portion (e.g., the electrodes) is directed toward theseptum. In yet other variations when the stimulators are used to treatnasal congestion, allergic rhinitis, non-allergic rhinitis, ocularallergy, and/or symptoms associated with these conditions, it may bedesirable to direct the nasal insertion prongs such that a portion(e.g., the electrodes) is directed outward and away from the septum.

Electrical Stimulus

In some variations, the stimulation may be delivered unilaterally (e.g.,in a single nostril). For example, in variations where a stimulatorcomprises a single prong, the prong may be placed in a first nostril,and stimulation may be delivered to the first nostril via the prong. Itshould be appreciated that in some of these variations in which thestimulus is electrical, a pad electrode or other return electrode may betemporarily affixed to or otherwise be placed in contact with anexternal portion of the nose to act as a return electrode. In somevariations where a stimulator comprises two or more prongs, each of theprongs may be placed in a first nostril, and some or all of the prongsmay be used to deliver stimulation to mucosal tissue. In othervariations where a stimulator comprises two or more prongs, at least oneprong may be positioned in a first nostril, and at least one prong maybe positioned in a second nostril. In variations in which the stimulusis electrical, some or all of the prongs in the first nostril may beused to deliver unilateral electrical stimulation to the first nostril(e.g., the prongs in the second nostril may remain inactive), or some orall of the prongs in the second nostril may be used to deliverunilateral electrical stimulation to the second nostril.

In some variations, the stimulator may be used to provide bilateralstimulation of the mucosal tissue. In these variations, at least oneprong of the stimulator may be positioned in a first nostril and atleast one prong of the stimulator may be positioned in a second nostril.In these variations, when the stimulus is electrical, electricalstimulation may be delivered between the prongs in the first nostril andthe prongs of the second nostril, which may cause current to flowthrough the septum.

When the stimulus is electrical, the electrical stimulus delivered bythe stimulators described here may include a waveform or waveforms,which may be tailored for specific treatment regimens and/or specificsubjects. The waveforms may be pulse-based or continuous. It should beappreciated that the waveforms described here may be delivered via abipolar configuration or a monopolar configuration. When the stimulatoris configured to deliver a continuous waveform, the waveform may be asinusoidal, quasi-sinusoidal, square-wave, sawtooth/ramped, ortriangular waveform, truncated-versions thereof (e.g., where thewaveform plateaus when a certain amplitude is reached), or the like.Generally, the frequency and peak-to-peak amplitude of the waveforms maybe constant, but in some variations the stimulator may be configured tovary the frequency and/or amplitude of the waveform. This variation mayoccur according to a pre-determined plan, or may be configured to occurrandomly within given parameters. For example, in some variations thecontinuous waveform may be configured such that the peak-to-peakamplitude of the waveform varies over time (e.g., according to asinusoidal function having a beat frequency). In some instances varyingthe amplitude and/or frequency of a stimulation waveform over time, orpulsing the stimulus on and off (e.g., 1 second on/1 second off, 5seconds on/5 seconds off), may help reduce subject habituation (in whichthe subject response to the stimulation decreases during stimulation).Additionally or alternatively, ramping the amplitude of the stimulationwaveform at the beginning of stimulation may increase comfort.

When the stimulator is configured to create a pulse-based electricalwaveform, the pulses may be any suitable pulses (e.g., a square pulse, ahaversine pulse, or the like). The pulses delivered by these waveformsmay by biphasic, alternating monophasic, or monophasic, or the like.When a pulse is biphasic, the pulse may include a pair of single phaseportions having opposite polarities (e.g., a first phase and acharge-balancing phase having an opposite polarity of the first phase).In some variations, it may be desirable to configure the biphasic pulseto be charge-balanced, so that the net charge delivered by the biphasicpulse is approximately zero. In some variations, a biphasic pulse may besymmetric, such that the first phase and the charge-balancing phase havethe same pulse width and amplitude. Having a symmetric biphasic pulsemay allow the same type of stimulus to be delivered to each nasalcavity. The pulses of a first phase may stimulate a first side of thenose (while providing a charge-balancing phase to a second side of thenose), while the pulses of the opposite phase may stimulate the secondside of the nose (while providing a charge-balancing phase to the firstside of the nose). In other variations, a biphasic pulse may beasymmetric, where the amplitude and/or pulse width of the first pulsemay differ from that of the charge-balancing phase. Additionally, eachphase of the biphasic pulse may be either voltage-controlled orcurrent-controlled. In some variations, both the first phase and thecharge-balancing phase of the biphasic pulse may be current-controlled.In other variations, both the first phase and the charge-balancing phaseof the biphasic pulse may be voltage-controlled. In still othervariations, the first phase of the biphasic pulse may becurrent-controlled, and the second phase of the biphasic pulse may bevoltage-controlled, or vice-versa.

In variations where the waveform comprises a biphasic pulse, thebiphasic pulse may have any suitable frequency, pulse widths, andamplitudes. For example, in instances where the stimulators describedhere are used to treat allergic rhinitis, non-allergic rhinitis, nasalcongestion, ocular allergy, and/or symptoms associated with theseconditions by stimulating nasal or sinus tissue, the stimulator may beconfigured to generate a biphasic pulse waveform at a frequency betweenabout 0.1 Hz and about 200 Hz. In some of these variations, thefrequency is preferably between about 10 Hz and about 60 Hz. In some ofthese variations, the frequency is preferably between about 25 Hz andabout 35 Hz. In others of these variations, the frequency is preferablybetween about 50 Hz and about 90 Hz. In some of these variations, thefrequency is preferably between about 65 Hz and about 75 Hz. In othervariations, the frequency is preferably between about 130 Hz and about170 Hz. In some of these variations, the frequency is preferably betweenabout 145 Hz and about 155 Hz. In some variations, high frequencies,such as those between about 145 Hz and about 155 Hz may be too high foreach pulse to stimulate/activate the target nerves. As a result, thestimulation may be interpreted by the patient to have an element ofrandomness, which in turn may help to reduce subject habituation.

Similarly, for the treatment of nasal congestion, allergic rhinitis,non-allergic rhinitis, ocular allergy, and/or symptoms associated withthese conditions when the stimulus is electrical and the first phase ofthe biphasic pulse is current-controlled, the first phase may preferablyhave an amplitude between about 10 μA and 100 mA. In some of thesevariations, the amplitude may be preferably between about 0.1 mA andabout 10 mA. When the first phase of the biphasic pulse isvoltage-controlled, the first phase may preferably have an amplitudebetween about 10 mV and about 100 V. Additionally, the first phase maypreferably have a pulse width between about 1 μs and about 10 ms. Insome of these variations, the pulse width may preferably be betweenabout 10 μs and about 100 μs. In other variations, the pulse width maypreferably be between about 100 μs and about 1 ms.

When an electrical pulse waveform is an alternating monophasic pulsedwaveform, each pulse delivered by the stimulator may have a singlephase, and successive pulses may have alternating polarities. Generally,the alternating monophasic pulses are delivered in pairs at a givenfrequency (such as one or more of the frequencies listed above, such asbetween 30 Hz and 50 Hz), and may have an inter-pulse interval betweenthe first and second pulse of the pair (e.g., about 100 μs, between 50μs and 150 μs or the like). Each pulse may be current-controlled orvoltage-controlled, and consecutive pulses need not be bothcurrent-controlled or both voltage-controlled. In some variations wherethe pulse waveform is charged-balanced, the waveform may comprise apassive charge-balancing phase after delivery of a pair of monophasicpulses, which may allow the waveform to compensate for chargedifferences between the pulses.

When a stimulator configured to deliver an electrical stimulus ispositioned to place an electrode on either side of the nasal septum,alternating monophasic pulses may promote bilateral stimulation of nasaltissue. The pulses of a first phase may stimulate a first side of thenose (while providing a charge-balancing phase to a second side of thenose), while the pulses of the opposite phase may stimulate the secondside of the nose (while providing a charge-balancing phase to the firstside of the nose), since nerves may respond differently to anodic andcathodic pulses. The inter-pulse interval may give time for thestimulation provided by a first phase pulse to activate/polarize thetarget nerves prior to be reversed by an opposite phase pulse.

When a stimulator is configured to deliver a pulse-based waveform, thestimulation amplitude, pulse width, and frequency may be the same frompulse to pulse, or may vary over time. For example, in some variations,the amplitude of the pulses may vary over time. In some variations, theamplitude of pulses may vary according to a sinusoidal profile. In somevariations, the stimulation waveform may be a modulated high frequencysignal (e.g., sinusoidal), which may be modulated at a beat frequency ofthe ranges described above. In such variations, the carrier frequencymay be between about 100 Hz and about 100 kHz. In other variations, theamplitude of pulses may increase (linearly, exponentially, etc.) from aminimum value to a maximum value, drop to the minimum value, and repeatas necessary. In some variations, the user may be able to control thestimulus during its delivery. After the user has placed a portion of thenasal insertion prong(s) (e.g., the electrode or electrodes) in contactwith the nasal tissue, the user may increase the intensity of thestimulus. It may be desirable for the patient to increase the intensityof the stimulus until the stimulus causes paresthesia (e.g., tingling,tickling, prickling). As such, the patient may be able to self-determinethe proper stimulation intensity and self-adjust the stimulus to a leveleffective to achieve the desired result. The desired result or treatmenteffect may depend on the condition to be treated. For example, thedesired result may be relief of symptoms of allergic rhinitis,non-allergic rhinitis, nasal congestion, and/or ocular allergy. In somevariations of a method for treatment of allergic rhinitis, for example,the treatment effect may comprise tear and/or mucous production. In somevariations of a method for treatment of non-allergic rhinitis, forexample, the treatment effect may comprise reduction in thickness and/orvolume of lamina propia tissue. It may be desirable for the user toincrease the intensity of the stimulus slowly in order to minimizediscomfort.

In some instances, it may be desirable to configure the stimulationwaveform to minimize side effects. In some instances, it may bedesirable to promote stimulation of larger-diameter nerves (e.g.,afferent fibers of the trigeminal nerve), which may promote atherapeutic effect, while reducing the stimulation of smaller nerves(e.g., a-delta fibers, c fibers, sympathetic and parasympatheticfibers), which may result in discomfort or mucus production. Generally,for smaller pulse-widths, the activation threshold for larger-diameternerves may be lower than the activation threshold for the smaller nervefibers. Conversely, for larger pulse-widths, the activation thresholdfor larger-diameter nerves may be higher than the activation thresholdfor the smaller nerve fibers. Accordingly, in some instances, it may bedesirable to select a pulse width that preferably actuations thelarger-diameter nerves. In some variations, the pulse width may bebetween 30 μs and about 70 μs, or may be between about 30 μs and about150 μs. However, it should be appreciated that in some variations, itmay be desirable to promote stimulation of nerves of other diameters. Insome variations it may be desirable to select a pulse width less than 30μs, and in other variations it may be desirable to select a pulse widthgreater than 150 μs.

While certain stimuli have been described herein, it should beappreciated that when used for treating nasal congestion, allergicrhinitis, non-allergic rhinitis, ocular allergy, and/or symptomsassociated with these conditions, the stimulation devices describedherein may deliver any suitable stimulus, including suitable stimulidescribed in U.S. application Ser. No. 14/256,915, filed Apr. 18, 2014,and titled “NASAL STIMULATION DEVICES AND METHODS,” which was previouslyincorporated by reference in its entirety, in U.S. application Ser. No.14/809,109, filed Jul. 24, 2015, and titled “STIMULATION PATTERNS FORTREATING DRY EYE,” which is hereby incorporated by reference in itsentirety, and in U.S. application Ser. No. 14/920,860, filed Oct. 22,2015, and titled “STIMULATION DEVICES AND METHODS FOR TREATING DRY EYE,”which was previously incorporated by reference in its entirety.Additionally, although the stimulation systems, devices, and methodsdescribed are herein are intended for use with human users, it should beappreciated that they may be modified for veterinary use.

Treatment Regimens

The stimulation methods described herein may be delivered according toone or more treatment regimens to treat a condition.

For example, to treat rhinitis (allergic rhinitis or non-allergicrhinitis), stimulation may in some variations be delivered to a subjectas needed and/or according to a pre-determined regimen. In someinstances, a user may use one of the stimulation devices describedherein to provide a round of stimulation when the user experiencessymptoms of allergic rhinitis and/or non-allergic rhinitis, such as butnot limited to itching, sneezing, congestion, subject sensation of“fullness,” runny nose, post-nasal drip, mouth breathing, coughing,fatigue, headache, anosmia, phlegm, throat irritation, periorbitalpuffiness, watery eyes, ear pain, or the like. In some variations, around of stimulation may have a suitable duration, such as but notlimited to between about 5 seconds and about 180 seconds, or betweenabout 10 seconds and about 60 seconds. In other variations, a user maydeliver a round of stimulation until the user notices an acute reductionin symptoms. When stimulation is delivered on an as-needed basis, a usermay deliver any suitable number of rounds of stimulation per day. Insome variations, the total number of rounds of stimulation may belimited to 10 per day. In other variations of methods to treat allergicrhinitis or non-allergic rhinitis, the devices described herein may beused to provide stimulation on a scheduled basis. For example, in somevariations in which the stimulation devices described herein are used totreat allergic rhinitis or non-allergic rhinitis, a round of stimulationmay be delivered between 2 and 10 times per day, for a plurality ofdays, on a regular pattern. Such a pattern may be, for example, every 12hours, every 8 hours, every 6 waking hours, every 4 waking hours, every3 waking hours, every 2 waking hours, every 1.5 waking hours, or thelike. In yet other variations of methods to treat allergic rhinitis,stimulation may be delivered both on a scheduled basis and in responseto symptoms of allergic rhinitis or non-allergic rhinitis. In somevariations of methods to treat allergic rhinitis, the methods maycomprise delivery of stimulation in combination with nose blowing. Forexample, a user may blow his or her nose after a round of stimulation,or a user may pause stimulus delivery one or more times to blow his orher nose during a round of stimulation. Nose blowing may expel anymaterial accumulated in the nasal passageways during stimulation, suchas a buildup of tear secretions and/or mucus. In the case of allergicrhinitis, expelling this accumulated material may contribute to flushingof allergens out of the nose.

As another example, to treat nasal congestion, stimulation may in somevariations be delivered to a subject as needed and/or according to apre-determined regimen. In some instances, a user may use one of thestimulation devices described herein to provide a round of stimulationwhen the user experiences symptoms of nasal congestion, such as but notlimited to difficulty with nasal breathing, ear fullness, facial pain,facial and/or intracranial pressure, decreased sense of smell and/ortaste, dizziness, post-nasal discharge, and/or thick nasal discharge. Insome variations, a round of stimulation may have a suitable duration,such as but not limited to between about 5 seconds and about 180seconds, or between about 10 seconds and about 60 seconds. In othervariations, a user may deliver a round of stimulation until the usernotices an acute reduction in symptoms. When stimulation is delivered onan as-needed basis, a user may deliver any suitable number of rounds ofstimulation per day. In some variations, the total number of rounds ofstimulation may be limited to 10 per day. In other variations of methodsto treat nasal congestion, the devices described herein may be used toprovide stimulation on a scheduled basis. For example, in somevariations in which the stimulation devices described herein are used totreat nasal congestion, a round of stimulation may be delivered between2 and 10 times per day, for a plurality of days, on a regular pattern.Such a pattern may be, for example, every 12 hours, every 8 hours, every6 waking hours, every 4 waking hours, every 3 waking hours, every 2waking hours, every 1.5 waking hours, or the like. In yet othervariations of methods to treat nasal congestion, stimulation may bedelivered both on a scheduled basis and in response to symptoms of nasalcongestion.

As another example, to treat ocular allergy, stimulation may in somevariations be delivered to a subject as needed and/or according to apre-determined regimen. In some instances, a user may use one of thestimulation devices described herein to provide a round of stimulationwhen the user experiences symptoms of ocular allergy, such as but notlimited to swelling or puffiness, itching, tearing, and/or discharge. Insome variations, a round of stimulation may have a suitable duration,such as but not limited to between about 5 seconds and about 180seconds, or between about 10 seconds and about 60 seconds. In othervariations, a user may deliver a round of stimulation until a desiredeffect occurs (e.g., increased tearing). When stimulation is deliveredon an as-needed basis, a user may deliver any suitable number of roundsof stimulation per day. In some variations, the total number of roundsof stimulation may be limited to 10 per day. In other variations ofmethods to treat ocular allergy, the devices described herein may beused to provide stimulation on a scheduled basis. For example, in somevariations in which the stimulation devices described herein are used totreat ocular allergy, a round of stimulation may be delivered between 2and 10 times per day, for a plurality of days, on a regular pattern.Such a pattern may be, for example, every 12 hours, every 8 hours, every6 waking hours, every 4 waking hours, every 3 waking hours, every 2waking hours, every 1.5 waking hours, or the like. In yet othervariations of methods to treat ocular allergy, stimulation may bedelivered both on a scheduled basis and in response to symptoms ofocular allergy.

It should be appreciated that the methods described herein may comprisedelivering a stimulus as described herein according to other suitabletreatment regimens for treating allergic rhinitis, non-allergicrhinitis, nasal congestion, ocular allergy, and/or symptoms associatedwith these conditions. For example, stimuli may be delivered at leastonce daily, at least once weekly, or the like. In some variations, thestimulation devices may be used to deliver multiple rounds ofstimulation each day (e.g., at least two treatments daily, at leastthree treatments daily, at least four treatments daily, at least fivetreatments daily, at least six treatments daily, at least seventreatments daily, at least eight treatments daily, between two and tentimes daily, between four and eight times daily, or the like). In somevariations, the stimulation may be delivered at certain times of day. Inother variations, the stimulation may be delivered at any time duringthe day as desired or determined by the user. When the device is used toprovide stimulation on a scheduled basis, in some variations each roundof stimulation may be the same length (e.g., about 30 seconds, about 1minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5minutes, about 10 minutes, or longer than 10 minutes). In othervariations, some rounds of stimulation may have different predeterminedlengths. In yet other variations, the user may choose the length of theround of stimulation. In some of these variations, the user may be givena minimum stimulation time (e.g., about 5 seconds, about 10 seconds,about 30 seconds, about 1 minute, about 2 minutes, about 3 minutes,about 5 minutes, or the like) and/or a maximum stimulation time (e.g.,about 1 minute, about 2 minutes, about 3 minutes, about 5 minutes, about10 minutes, about 20 minutes, or the like). In some instances, thedelivery schedule or stimulation parameters may be changed based on thetime of day (e.g., daytime use vs. nighttime use). In some of thesevariations, the stimulator may comprise (e.g., as part of a controlsubsystem) one or more counters and intelligence (e.g., amicrocontroller, programmable logic (e.g., a field-programmable gatearray), or application-specific integrated circuit (ASIC)). Othertreatment regimens that may be used for the methods described herein mayinclude suitable treatment regimens described in U.S. application Ser.No. 14/256,915, filed Apr. 18, 2014, and titled “NASAL STIMULATIONDEVICES AND METHODS,” which was previously incorporated by reference inits entirety.

In some variations, methods may comprise delivering a stimulus asdescribed herein in combination with other forms of therapy for allergicrhinitis, non-allergic rhinitis, nasal congestion, ocular allergy,and/or symptoms associated with these conditions. For example, in somevariations the methods may comprise delivering a stimulus in combinationwith pharmacologic therapy, such as but not limited to intranasalsteroids, oral antihistamines, or anti-IgE. This combined approach maybe beneficial as compared to pharmacologic therapy alone due to reduceddurations and/or reduced dosages of pharmacologic therapy, which may inturn result in improved safety profiles (i.e., reduced unwanted sideeffects from such pharmacologic therapy).

Treatment Effects

In some variations, the treatment regimens described herein may be usedto treat rhinitis, including allergic rhinitis (acute and/or chronic)and/or non-allergic rhinitis (acute and/or chronic), nasal congestion,ocular allergy, and/or symptoms associated with these conditions. Incontrast to current treatment options, the treatment regimens using thestimulators described herein may provide rapid and marked improvement inobjective measures of health and symptomatic relief, and may have fewerunwanted side effects. In some variations, the treatment regimens ofproviding the stimuli described herein may cause periodic or regularactivation of the nasolacrimal reflex, which may in turn treat allergicrhinitis, non-allergic rhinitis, nasal congestion, ocular allergy,and/or the symptoms associated with these conditions.

In some variations, the treatment methods described herein for treatingallergic rhinitis may result in improvements in measurements of one ormore of the thickness and/or volume of lamina propia tissue (e.g., asmeasured by direct visual examination of the sinus cavity (e.g., byendoscopic examination or speculum examination), use of imagingmodalities such as CT or MRI, or the like); redness of nasal mucosa;thickness and/or volume of clear airway passages (e.g., as measured bydirect visual examination of the sinus cavity (e.g., by endoscopicexamination or speculum examination), use of imaging modalities such asCT or MRI, or the like); microbiological assessment of sinus aspirate;degree of inflammation of nasal mucosa; nasal fractional exhaled nitricoxide; peak nasal inspiratory flow; acute and/or chronic change in nasaldischarge volume; viscosity of nasal discharge; nasal airwayresistance/impedance; rhinorrhea (runny nose); post-nasal drip;sneezing; nasal congestion; mouth breathing; coughing; headache;anosmia; phlegm volume; itchiness; and/or pain.

In some variations, the treatment methods described herein for treatingnon-allergic rhinitis may result in improvements in measures of one ormore of the thickness and/or volume of lamina propia tissue (e.g., asmeasured by direct visual examination of the sinus cavity (e.g., byendoscopic examination or speculum examination), use of imagingmodalities such as CT or MRI, or the like); redness of nasal mucosa;thickness and/or volume of clear airway passages (e.g., as measured bydirect visual examination of the sinus cavity (e.g., by endoscopicexamination or speculum examination), use of imaging modalities such asCT or MRI, or the like); microbiological assessment of sinus aspirate;degree of inflammation of nasal mucosa; degree of inflammation of nasalmucosa; nasal fractional exhaled nitric oxide; peak nasal inspiratoryflow; acute and/or chronic change in nasal discharge volume; viscosityof nasal discharge; nasal airway resistance/impedance; rhinorrhea (runnynose); post-nasal drip; sneezing; nasal congestion; mouth breathing;coughing; headache; anosmia; phlegm volume; itchiness; and/or pain.

In some variations, the treatment methods described herein for treatingnasal congestion may result in improvements in measures of one or moreof the thickness and/or volume of lamina propia tissue (e.g., asmeasured by direct visual examination of the sinus cavity (e.g., byendoscopic examination or speculum examination), use of imagingmodalities such as CT or MRI, or the like); redness of nasal mucosa;thickness and/or volume of clear airway passages (e.g., as measured bydirect visual examination of the sinus cavity (e.g., by endoscopicexamination or speculum examination), use of imaging modalities such asCT or MRI, or the like); stuffy nose; and/or breathing through themouth.

In some variations, the treatment methods described herein for treatingocular allergy may result in improvements in measures of one or more ofitching; chemosis; eyelid swelling; excessive tearing; foreign bodysensation; and/or ocular discomfort.

Example

A study will be carried out to explore the effectiveness of electricalstimulation as described herein for the treatment of symptoms ofallergic rhinitis.

Participants will be randomized between 1 of 2 treatment sequences. In afirst sequence, participants will use an interventional device to applyintranasal electrical stimulation during a first visit, and will use acontrol device during a second visit. In a second sequence, participantswill use a control device during a first visit, and will use aninterventional device to apply intranasal electrical stimulation duringa second visit. The interventional and control devices will be visuallyidentical, but only the interventional device will generate electricalstimulation. The control device will apply only mechanical stimulation.The interventional device will be applied in the upper part of the nosein order to stimulate the nasolacrimal reflex pathways by gentlyactivating the anterior ethmoidal nerve, a sub-branch of the ophthalmicbranch of the trigeminal nerve that provides neural input to thesuperior salivatory nucleus in the brainstem, as shown in FIG. 11A. Thecontrol device will be applied only in the lower part of the nose toavoid activation of the nasolacrimal reflex, as shown in FIG. 11B.Randomization will be stratified by type of allergy (seasonal versusperennial). During the treatment sequences, participants will applyelectrical/mechanical stimulation with the interventional device/controldevice for 3 minutes.

The interventional device will comprise a device having features shownand described with respect to FIGS. 1A-1E. The interventional devicewill comprise a reusable stimulator body configured to generate anelectrical stimulus, and a disposable stimulator probe attachable to thestimulator body. The stimulator probe will comprise two nasal insertionprongs configured to be inserted into a participant's nasal cavity, witheach prong comprising a hydrogel electrode. The stimulator body willcomprise a user interface comprising two buttons, which will allow theparticipant to turn on the stimulator and change the stimulusparameters, and light-emitting diodes to indicate the stimulation levelbeing delivered. The interventional device will further include acharger configured to recharge a battery within the stimulator body anda reusable cover configured to be placed over and protect the stimulatorprobe.

The stimulator body will be configured to deliver five different levelsof stimulation. Setting 1 will have a stimulation frequency of 30 Hz; aminimum stimulation current amplitude of 0.7 mA, a maximum stimulationcurrent amplitude of 0.7 mA, and thus no variation in maximumstimulation current amplitude; a minimum pulse width of 0 μs; a maximumpulse width of 300 μs; a pulse width modulation frequency of 1 Hz(rising and falling according to an exponential function); a minimumcharge injection per phase (at 0 μs pulse width) of 0 μC; a maximumcharge injection per phase (at 0.7 mA and 300 μs) of 0.21 μC; and apulse shape that is cycled between four periods. The first period willcomprise a two-phase current-controlled waveform with symmetricalphases. The second period will comprise a current-controlled firstphase, followed by a voltage-controlled second phase. The first phasewill have a current sourced by a first electrode and sunk by a secondelectrode, while the second phase will have a current sourced by thesecond electrode and sunk by the first electrode. The third period willcomprise a two-phase current-controlled waveform with symmetrical phases(i.e., the third period may be the same as the first period). The fourthperiod will comprise a current-controlled first phase, followed by avoltage-controlled second phase. The first phase will have a currentsourced by the second electrode and sunk by the first electrode, whilethe second phase will have a current sourced by the first electrode andsunk by the second electrode. In each period, the pulses will becharged-balanced. Setting 2 will have a stimulation frequency of 37.5Hz; a minimum stimulation current amplitude of 1.33 mA, a maximumstimulation current amplitude of 1.5 mA, a variation in maximumstimulation current amplitude of 0.17 mA, and an amplitude modulationfrequency of 2.1 Hz; a minimum pulse width of 0 μs; a maximum pulsewidth of 300 μs; a pulse width modulation frequency of 1 Hz (rising andfalling according to an exponential function); a minimum chargeinjection per phase (at 0 μs pulse width) of 0 μC; a maximum chargeinjection per phase (at 1.5 mA and 300 μs) of 0.45 μC; and a pulse shapethat is modulated as described above with respect to Setting 1. Setting3 will have a stimulation frequency of 45 Hz; a minimum stimulationcurrent amplitude of 2.17 mA, a maximum stimulation current amplitude of2.5 mA, a variation in maximum stimulation current amplitude of 0.33 mA,and an amplitude modulation frequency of 2.6 Hz; a minimum pulse widthof 0 μs; a maximum pulse width of 300 μs; a pulse width modulationfrequency of 1 Hz (rising and falling according to an exponentialfunction); a minimum charge injection per phase (at 0 μs pulse width) of0 μC; a maximum charge injection per phase (at 2.5 mA and 300 μs) of0.75 μC; and a pulse shape that is modulated as described above withrespect to Setting 1. Setting 4 will have a stimulation frequency of52.5 Hz; a minimum stimulation current amplitude of 3.2 mA, a maximumstimulation current amplitude of 3.7 mA, a variation in maximumstimulation current amplitude of 0.5 mA, and an amplitude modulationfrequency of 2.8 Hz; a minimum pulse width of 0 μs; a maximum pulsewidth of 300 μs; a pulse width modulation frequency of 1 Hz (rising andfalling according to an exponential function); a minimum chargeinjection per phase (at 0 μs pulse width) of 0 μC; a maximum chargeinjection per phase (at 3.7 mA and 300 μs) of 1.11 μC; and a pulse shapethat is modulated as described above with respect to Setting 1. Setting5 will have a stimulation frequency of 60 Hz; a minimum stimulationcurrent amplitude of 4.3 mA, a maximum stimulation current amplitude of5.0 mA, a variation in maximum stimulation current amplitude of 0.67 mA,and an amplitude modulation frequency of 2.5 Hz; a minimum pulse widthof 0 μs; a maximum pulse width of 300 μs; a pulse width modulationfrequency of 1 Hz (rising and falling according to an exponentialfunction); a minimum charge injection per phase (at 0 μs pulse width) of0 μC; a maximum charge injection per phase (at 5.0 mA and 300 μs) of 1.5μC; and a pulse shape that is modulated as described above with respectto Setting 1. The control device will look identical to theinterventional device, but will not deliver electrical stimulation.

A number of measures of effectiveness of intranasal stimulation fortreatment of the symptoms of allergic rhinitis will be used. Measureswill include participant-assessed allergic rhinitis symptom score, nasalinflammation score, peak nasal inspiratory flow, mass of nasalsecretions, nasal thermal scan (used as a surrogate marker ofinflammatory changes of the nasal cavity), and nasal fractional exhalednitric oxide (an increase in fractional exhaled nitric oxide may reflecta permanent inflammation of the sinus mucosa).

Allergic rhinitis symptom score: Each participant will evaluate fourallergic rhinitis symptoms, including nasal itching, nasal congestion,rhinorrhea, and sneezing on a 0 to 3 scale (0=no sign/symptom isevident; 1=sign/symptom clearly present, but minimal awareness—easilytolerated; 2=definite awareness of sign/symptom that is bothersome, buttolerable; 3=sign/symptom that is hard to tolerate; causes interferencewith activities). Symptoms will be evaluated at 5±1 minutes before nasalstimulation, and at 5±1, 10±1, 15±1, 20±1, 30±1, 45±1, 60±5, 75±5, 90±5,105±5, 120±5, 135±5, 150±5, 165±5, and 180±5 minutes after nasalstimulation. It is hypothesized that a composite score (sum) of the foursymptoms (nasal itching, nasal congestion, rhinorrhea, and sneezing)will be lower after intranasal electrical stimulation than prior tostimulation. It is hypothesized that activation of the nasolacrimalreflex, via stimulus delivery to the anterior ethmoidal nerve, willinduce increased rhinorrhea and a local sympathetic rebound leading tovasoconstriction in the nasal cavity. Together, increased rhinorrhea andlocal vasoconstriction will lead to a relief of symptoms usuallyassociated with allergic rhinitis.

Nasal inflammation score: Nasal inflammation score will be evaluated byan investigator on a 0 to 4 scale using nasal digital videos of eachnostril, where characteristics of redness, swelling, and abnormal nasalsecretions will be evaluated. Nasal inflammation will be evaluated priorto stimulation (within 30 minutes prior to the first evaluation ofsymptoms at −5±1 minutes before stimulation) and at 180±5 minutes afternasal stimulation. It is hypothesized that nasal inflammation willdecrease after intranasal electrical stimulation.

Peak nasal inspiratory flow: Nasal peak inspiratory flow readings willbe made using an inspiratory flow meter with nasal adaptor. Measurementswill be made in a standing position. Subjects will be instructed toexhale residual volume, place a face mask over the mouth and nose tocreate a good seal around the face mask, and then inhale forcefully tototal lung capacity, through the nose, with mouth closed. This maneuvershould be a short, sharp inspiratory action of about 1 second induration. Peak nasal inspiratory flow will be evaluated prior tostimulation (within 30 minutes prior to the first evaluation of symptomsat −5±1 minutes before stimulation) and at 60±5, 120±5, and 180±5minutes after stimulation. Three measurements will be made at each timepoint. It is hypothesized that peak nasal inspiratory flow over the timepoints will initially transiently decrease, and then increase.

Mass of nasal secretions: Each subject will be given a bag ofpre-weighed disposable tissues to use during the course of eachmeasurement period. Used tissues will be placed in a closed disposableplastic container, as to minimize evaporation. The container of bothused and unused tissues will be weighed after the measurement period iscomplete and the mass increase, if any, due to nasal secretions will berecorded. The mass of nasal secretions will be measured prior tostimulation (within 30 minutes prior to the first evaluation of symptomsat −5±1 minutes before stimulation), and at 10±1, 60±5, 120±5, and 180±5minutes after stimulation. It is hypothesized that the mass of nasalsecretions over the time points will initially transiently increase, andthen decrease.

Nasal thermal scan: For nasal thermal scanning, the temperature of thetissue surrounding the nasal area will be measured as a surrogate forinflammation. A thermal camera will be used to capture thermal images ofthe nasal area. The temperature of the tissue will be recorded toidentify when an allergic response causing vasodilatation is occurring,as identified by an acute increase in temperature. Nasal thermal scanswill be conducted prior to stimulation (within 30 minutes prior to thefirst evaluation of symptoms at −5±1 minutes before stimulation), and at15±1, 30±1, 45±1, 60±5, 90±5, 120±5, 150±5, and 180±5 minutes afterstimulation. When thermal scans are conducted at the same time point ascollection of nasal secretions, the thermal image will be taken beforethe collection of nasal secretions. It is hypothesized that stimulationwill result in more rapid temperature normalization.

Nasal fractional exhaled nitric oxide: A fractional exhaled nitricoxide-sensing machine will be used to measure nitric oxide levels fromexhalation. Fractional exhaled nitric oxide will be evaluated prior tostimulation (within 30 minutes prior to the first evaluation of symptomsat −5±1 minutes before stimulation), and at 30±1, 60±5, 90±5, 120±5,150±5, and 180±5 minutes after stimulation. It is expected that levelsof nitric oxide will increase as the tissue undergoes an eosinophilicresponse to the allergen, and that stimulation will result in decreasednasal fractional exhaled nitric oxide.

The invention claimed is:
 1. A method for treating an ocular condition,the method comprising: contacting a stimulating portion of a handheldstimulator to external nasal tissue of a nose of a subject, thestimulating portion extending from a stimulator body of the handheldstimulator; and delivering a stimulus via the stimulating portion to theexternal nasal tissue to activate an anterior ethmoidal nerve, therebyimproving the ocular condition of the subject, wherein the stimulatorbody of the handheld stimulator comprises a control subsystem to controlthe stimulus.
 2. The method of claim 1, wherein the stimulus isdelivered in response to one or more symptoms of the ocular condition.3. The method of claim 2, wherein the one or more symptoms of the ocularcondition comprise one or more of itching, sneezing, congestion, runnynose, post-nasal drip, mouth breathing, coughing, fatigue, headache,anosmia, phlegm, throat irritation, periorbital puffiness, watery eyes,ear pain, and fullness sensation.
 4. The method of claim 1, wherein theocular condition comprises rhinitis.
 5. The method of claim 1, whereinthe ocular condition comprises an ocular allergy.
 6. The method of claim1, wherein the stimulus is delivered more than once per day on ascheduled basis.
 7. The method of claim 1, wherein the stimulatingportion comprises a first electrode and a second electrode.
 8. Themethod of claim 1, wherein the stimulus is a biphasic pulse waveform. 9.The method of claim 8, wherein the biphasic pulse waveform issymmetrical.
 10. The method of claim 8, wherein the biphasic pulsewaveform has a varying peak to peak amplitude.
 11. The method of claim8, wherein the biphasic pulse waveform has a varying frequency.
 12. Themethod of claim 1, wherein the stimulus is pulsed.
 13. The method ofclaim 1, wherein the stimulating portion is releasably coupled to thestimulator body.
 14. A method for treating an ocular condition, themethod comprising: contacting an electrode of a handheld stimulator toexternal nasal skin of a nose of a subject, the electrode being coupledto a stimulator body of the handheld stimulator; and delivering anelectrical stimulus via the electrode to the external nasal skin of thesubject to activate an anterior ethmoidal nerve, thereby improving theocular condition of the subject.
 15. The method of claim 14, wherein theelectrical stimulus is delivered in response to one or more symptoms ofthe ocular condition.
 16. The method of claim 15, wherein the one ormore symptoms of the ocular condition comprise one or more of itching,sneezing, congestion, runny nose, post-nasal drip, mouth breathing,coughing, fatigue, headache, anosmia, phlegm, throat irritation,periorbital puffiness, watery eyes, ear pain, and fullness sensation.17. The method of claim 15, wherein the electrical stimulus is abiphasic pulse waveform.
 18. The method of claim 14, wherein the ocularcondition comprises rhinitis.
 19. The method of claim 14, wherein theocular condition comprises an ocular allergy.
 20. The method of claim14, wherein the electrical stimulus is delivered more than once per dayon a scheduled basis.
 21. The method of claim 14, wherein the electricalstimulus is pulsed.
 22. The method of claim 21, wherein the biphasicpulse waveform is symmetrical.
 23. The method of claim 21, wherein thebiphasic pulse waveform has a varying peak to peak amplitude.
 24. Themethod of claim 21, wherein the biphasic pulse waveform has a varyingfrequency.
 25. The method of claim 14, wherein the electrode isreleasably coupled to the stimulator body.